恶性肿瘤缺氧酸性微环境对免疫治疗影响机制的研究进展
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摘要
近年来,以免疫检查点阻断单克隆抗体和抗原受体T细胞免疫疗法细胞治疗为代表的免疫疗法在治疗恶性肿瘤方面取得突破性进展.然而,肿瘤通过各种不同的机制逃避免疫系统的识别和杀伤,导致免疫治疗效果仍不理想.由癌细胞、血管、淋巴、成纤维细胞、炎症细胞以及多种细胞外基质有机构成的肿瘤组织微环境不仅支持癌细胞的生长和转移,也影响免疫细胞识别和杀伤癌细胞以及迁移的功能,调控免疫效应分子的活化,从而影响免疫治疗的效果.实体肿瘤内异常血管网络和快速生长的癌细胞对氧过量需求导致肿瘤组织缺氧,并加剧由于癌细胞异常代谢导致肿瘤组织的酸性微环境.缺氧酸性微环境是肿瘤微环境最重要的组成部分,癌细胞适应和利用这些微环境,导致基因变异的多样性和不稳定性,激活多种信号通路和生存因子,造成肿瘤对包括免疫治疗在内的多种治疗方法的耐受和抵抗.本文针对近年来肿瘤缺氧酸性微环境对免疫治疗影响机制的研究进展进行述评,希望给从事癌症微环境和免疫治疗的临床基础科研人员提供新的思路.
Cancer immunotherapy has become one of the areas in which major medical breakthroughs are being witnessed. The recent promising progress in activating therapeutic anti-tumor immunity, such as checkpoint blockade and chimeric antigen receptor T-cell immuno therapy therapy, has made us closer to, but there is still a long way to reach, the final goal in the battle against cancer, since cancer cells utilize different mechanisms to escape from immune attack, leading to limited efficacy of immunotherapies in treating malignant tumors. Tumor tissues consist of cancer cells, blood vessels, lymphatic capillaries, fibroblasts, inflammatory cells and various types of extracellular matrixes, which compose tumor microenvironments. Tumor microenvironments not only support the growth and metastasis of cancer cells, but also affect the recognition and killing of cancer cells by immune cells and their ability to migrate and regulate the activation of effector molecules, thus influencing the therapeutic effects of immunotherapies. Tumor hypoxic microenvironments are caused by abnormal blood supply networks and outweighing demands of oxygen by fast dividing cancer cells. Hypoxia can also, together with abnormal metabolism of cancer cells, lead to sequential tumor acidic microenvironments. Hypoxic and acidic microenvironments are frequentlyobserved in almost all solid tumors, and adapted and exploited by cancer cells for their survival and invasion. Hypoxic and acidic microenvironments can also result in the diversity and instability of gene mutations and the activation of cellular signaling pathways and survival factors, and have been regarded as one of the major causes of the resistance to various therapies including immunotherapy. The present article summarizes the recent progress in the understanding of the mechanisms by which tumor hypoxic and acidic microenvironments influence immunotherapy, and analyzes the potential strategies for coping with these obstacles to combating cancer. We hope it can provide some new clues for clinicians and scientists engaged in the research areas of tumor microenvironments and immunotherapy.
Cancer immunotherapy has become one of the areas in which major medical breakthroughs are being witnessed. The recent promising progress in activating therapeutic anti-tumor immunity, such as checkpoint blockade and chimeric antigen receptor T-cell immuno therapy therapy, has made us closer to, but there is still a long way to reach, the final goal in the battle against cancer, since cancer cells utilize different mechanisms to escape from immune attack, leading to limited efficacy of immunotherapies in treating malignant tumors. Tumor tissues consist of cancer cells, blood vessels, lymphatic capillaries, fibroblasts, inflammatory cells and various types of extracellular matrixes, which compose tumor microenvironments. Tumor microenvironments not only support the growth and metastasis of cancer cells, but also affect the recognition and killing of cancer cells by immune cells and their ability to migrate and regulate the activation of effector molecules, thus influencing the therapeutic effects of immunotherapies. Tumor hypoxic microenvironments are caused by abnormal blood supply networks and outweighing demands of oxygen by fast dividing cancer cells. Hypoxia can also, together with abnormal metabolism of cancer cells, lead to sequential tumor acidic microenvironments. Hypoxic and acidic microenvironments are frequentlyobserved in almost all solid tumors, and adapted and exploited by cancer cells for their survival and invasion. Hypoxic and acidic microenvironments can also result in the diversity and instability of gene mutations and the activation of cellular signaling pathways and survival factors, and have been regarded as one of the major causes of the resistance to various therapies including immunotherapy. The present article summarizes the recent progress in the understanding of the mechanisms by which tumor hypoxic and acidic microenvironments influence immunotherapy, and analyzes the potential strategies for coping with these obstacles to combating cancer. We hope it can provide some new clues for clinicians and scientists engaged in the research areas of tumor microenvironments and immunotherapy.
引文
1 Coley WB.The treatment of malignant tumors by repeated inoculations of erysipelas.With a report of ten original cases.1893.Clin Orthop Relat Res1991;(262):3-11[PMID:1984929]
2 Klein G,Sjogren HO,Klein E,Hellstrom KE.Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host.Cancer Res 1960;20:1561-1572[PMID:13756652]
3 Burnet FM.Immunological aspects of malignant disease.Lancet 1967;1:1171-1174[PMID:4165129DOI:10.1016/S0140-6736(67)92837-1]
4 Mellman I,Coukos G,Dranoff G.Cancer immunotherapy comes of age.Nature 2011;480:480-489[PMID:22193102 DOI:10.1038/nature10673]
5 Melero I,Gaudernack G,Gerritsen W,Huber C,Parmiani G,Scholl S,Thatcher N,Wagstaff J,Zielinski C,Faulkner I,Mellstedt H.Therapeutic vaccines for cancer:an overview of clinical trials.Nat Rev Clin Oncol 2014;11:509-524[PMID:25001465 DOI:10.1038/nrclinonc.2014.111]
6 McNutt M.Cancer immunotherapy.Science2013;342:1417[PMID:24357273 DOI:10.1126/science.1249481]
7 Immunotherapy:combine and conquer.Nat Med2015;21:415[PMID:25951522 DOI:10.1038/nm.3865]
8 Sharma P,Allison JP.The future of immune checkpoint therapy.Science 2015;348:56-61[PMID:25838373 DOI:10.1126/science.aaa8172]
9 Lee DW,Kochenderfer JN,Stetler-Stevenson M,Cui YK,Delbrook C,Feldman SA,Fry TJ,Orentas R,Sabatino M,Shah NN,Steinberg SM,Stroncek D,Tschernia N,Yuan C,Zhang H,Zhang L,Rosenberg SA,Wayne AS,Mackall CL.T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults:a phase 1 dose-escalation trial.Lancet 2015;385:517-528[PMID:25319501 DOI:10.1016/S0140-6736(14)61403-3]
10 Turtle CJ,Hanafi LA,Berger C,Gooley TA,Cherian S,Hudecek M,Sommermeyer D,Melville K,Pender B,Budiarto TM,Robinson E,Steevens NN,Chaney C,Soma L,Chen X,Yeung C,Wood B,Li D,Cao J,Heimfeld S,Jensen MC,Riddell SR,Maloney DG.CD19 CAR-T cells of defined CD4+:CD8+composition in adult B cell ALL patients.JClin Invest 2016;126:2123-2138[PMID:27111235DOI:10.1172/JCI85309]
11 Topalian SL,Hodi FS,Brahmer JR,Gettinger SN,Smith DC,McDermott DF,Powderly JD,Carvajal RD,Sosman JA,Atkins MB,Leming PD,Spigel DR,Antonia SJ,Horn L,Drake CG,Pardoll DM,Chen L,Sharfman WH,Anders RA,Taube JM,McMiller TL,Xu H,Korman AJ,Jure-Kunkel M,Agrawal S,McDonald D,Kollia GD,Gupta A,Wigginton JM,Sznol M.Safety,activity,and immune correlates of antiPD-1 antibody in cancer.N Engl J Med 2012;366:2443-2454[PMID:22658127 DOI:10.1056/NEJMoa1200690]
12 Noman MZ,Messai Y,CarréT,Akalay I,Méron M,Janji B,Hasmim M,Chouaib S.Microenvironmental hypoxia orchestrating the cell stroma cross talk,tumor progression and antitumor response.Crit Rev Immunol 2011;31:357-377[PMID:22142164 DOI:10.1615/CritRevImmunol.v31.i5.10]
13 Klemm F,Joyce JA.Microenvironmental regulation of therapeutic response in cancer.Trends Cell Biol 2015;25:198-213[PMID:25540894DOI:10.1016/j.tcb.2014.11.006]
14 Nagelkerke A,Bussink J,Rowan AE,Span PN.The mechanical microenvironment in cancer:How physics affects tumours.Semin Cancer Biol2015;35:62-70[PMID:26343578 DOI:10.1016/j.semcancer.2015.09.001]
15 Marchiq I,Pouysségur J.Hypoxia,cancer metabolism and the therapeutic benefit of targeting lactate/H(+)symporters.J Mol Med(Berl)2016;94:155-171[PMID:26099350 DOI:10.1007/s00109-015-1307-x]
16 Pastorek J,Pastorekova S.Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy:from biology to clinical use.Semin Cancer Biol 2015;31:52-64[PMID:25117006 DOI:10.1016/j.semcancer.2014.08.002]
17 Barsoum IB,Smallwood CA,Siemens DR,Graham CH.A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.Cancer Res 2014;74:665-674[PMID:24336068DOI:10.1158/0008-5472.can-13-0992]
18 Noman MZ,Hasmim M,Messai Y,Terry S,Kieda C,Janji B,Chouaib S.Hypoxia:a key player in antitumor immune response.A Review in the Theme:Cellular Responses to Hypoxia.Am JPhysiol Cell Physiol 2015;309:C569-C579[PMID:26310815 DOI:10.1152/ajpcell.00207.2015]
19 Semenza GL.Hypoxia-inducible factors in physiology and medicine.Cell 2012;148:399-408[PMID:22304911 DOI:10.1016/j.cell.2012.01.021]
20 Thiel M,Chouker A,Ohta A,Jackson E,Caldwell C,Smith P,Lukashev D,Bittmann I,Sitkovsky MV.Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury.PLoSBiol 2005;3:e174[PMID:15857155 DOI:10.1371/journal.pbio.0030174]
21 Nakamura H,Makino Y,Okamoto K,Poellinger L,Ohnuma K,Morimoto C,Tanaka H.TCRengagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycinsensitive pathway under hypoxic conditions in human peripheral T cells.J Immunol 2005;174:7592-7599[PMID:15944259 DOI:10.4049/jimmunol.174.12.7592]
22 Tao JH,Barbi J,Pan F.Hypoxia-inducible factors in T lymphocyte differentiation and function.A Review in the Theme:Cellular Responses to Hypoxia.Am J Physiol Cell Physiol 2015;309:C580-C589[PMID:26354751 DOI:10.1152/ajpcell.00204.2015]
23 Phan AT,Goldrath AW.Hypoxia-inducible factors regulate T cell metabolism and function.Mol Immunol 2015;68:527-535[PMID:26298577DOI:10.1016/j.molimm.2015.08.004]
24 Doedens AL,Phan AT,Stradner MH,Fujimoto JK,Nguyen JV,Yang E,Johnson RS,Goldrath AW.Hypoxia-inducible factors enhance the effector responses of CD8(+)T cells to persistent antigen.Nat Immunol 2013;14:1173-1182[PMID:24076634 DOI:10.1038/ni.2714]
25 Finlay DK,Rosenzweig E,Sinclair LV,FeijooCarnero C,Hukelmann JL,Rolf J,Panteleyev AA,Okkenhaug K,Cantrell DA.PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+T cells.J Exp Med 2012;209:2441-2453[PMID:23183047 DOI:10.1084/jem.20112607]
26 Jiménez-Pérez L,Cidad P,álvarez-Miguel I,Santos-Hipólito A,Torres-Merino R,Alonso E,de la Fuente Má,López-López JR,Pérez-García MT.Molecular Determinants of Kv1.3 Potassium Channels-induced Proliferation.J Biol Chem 2016;291:3569-3580[PMID:26655221 DOI:10.1074/jbc.M115.678995]
27 Lukashev D,Klebanov B,Kojima H,Grinberg A,Ohta A,Berenfeld L,Wenger RH,Ohta A,Sitkovsky M.Cutting edge:hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+and CD8+T lymphocytes.J Immunol 2006;177:4962-4965[PMID:17015677 DOI:10.4049/jimmunol.177.8.4962]
28 Hoskin DW,Mader JS,Furlong SJ,Conrad DM,Blay J.Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells(Review).Int JOncol 2008;32:527-535[PMID:18292929 DOI:10.3892/ijo.32.3.527]
29 Deaglio S,Dwyer KM,Gao W,Friedman D,Usheva A,Erat A,Chen JF,Enjyoji K,Linden J,Oukka M,Kuchroo VK,Strom TB,Robson SC.Adenosine generation catalyzed by CD39and CD73 expressed on regulatory T cells mediates immune suppression.J Exp Med 2007;204:1257-1265[PMID:17502665 DOI:10.1084/jem.20062512]
30 Tan S,Bose R,Derrick M.Hypoxia-ischemia in fetal rabbit brain increases reactive nitrogen species production:quantitative estimation of nitrotyrosine.Free Radic Biol Med 2001;30:1045-1051[PMID:11316585 DOI:10.1016/S0891-5849(01)00499-3]
31 Nagaraj S,Gupta K,Pisarev V,Kinarsky L,Sherman S,Kang L,Herber DL,Schneck J,Gabrilovich DI.Altered recognition of antigen is a mechanism of CD8+T cell tolerance in cancer.Nat Med 2007;13:828-835[PMID:17603493 DOI:10.1038/nm1609]
32 Noman MZ,Chouaib S.Targeting hypoxia at the forefront of anticancer immune responses.Oncoimmunology 2014;3:e954463[PMID:25964858DOI:10.4161/21624011.2014.954463]
33 Noman MZ,Desantis G,Janji B,Hasmim M,Karray S,Dessen P,Bronte V,Chouaib S.PD-L1is a novel direct target of HIF-1α,and its blockade under hypoxia enhanced MDSC-mediated T cell activation.J Exp Med 2014;211:781-790[PMID:24778419 DOI:10.1084/jem.20131916]
34 Palazón A,Martínez-Forero I,Teijeira A,MoralesKastresana A,Alfaro C,Sanmamed MF,PerezGracia JL,Pe駏elas I,Hervás-Stubbs S,Rouzaut A,de Landázuri MO,Jure-Kunkel M,Aragonés J,Melero I.The HIF-1αhypoxia response in tumorinfiltrating T lymphocytes induces functional CD137(4-1BB)for immunotherapy.Cancer Discov 2012;2:608-623[PMID:22719018 DOI:10.1158/2159-8290.CD-11-0314]
35 Weigelin B,Bolanos E,Rodriguez-Ruiz ME,Martinez-Forero I,Friedl P,Melero I.AntiCD137 monoclonal antibodies and adoptive Tcell therapy:a perfect marriage?Cancer Immunol Immunother 2016;65:493-497[PMID:26970765DOI:10.1007/s00262-016-1818-5]
36 Muntasell A,Ochoa MC,Cordeiro L,Berraondo P,López-Díaz de Cerio A,Cabo M,López-Botet M,Melero I.Targeting NK-cell checkpoints for cancer immunotherapy.Curr Opin Immunol2017;45:73-81[PMID:28236750 DOI:10.1016/j.coi.2017.01.003]
37 Yamada N,Yamanegi K,Ohyama H,Hata M,Nakasho K,Futani H,Okamura H,Terada N.Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICAin osteosarcoma cells in a HIF-1α-dependent manner.Int J Oncol 2012;41:2005-2012[PMID:22992985 DOI:10.3892/ijo.2012.1630]
38 Abruzzese MP,Bilotta MT,Fionda C,Zingoni A,Soriani A,Vulpis E,Borrelli C,Zitti B,Petrucci MT,Ricciardi MR,Molfetta R,Paolini R,Santoni A,Cippitelli M.Inhibition of bromodomain and extra-terminal(BET)proteins increases NKG2Dligand MICA expression and sensitivity to NKcell-mediated cytotoxicity in multiple myeloma cells:role of cMYC-IRF4-miR-125b interplay.JHematol Oncol 2016;9:134[PMID:27903272 DOI:10.1186/s13045-016-0362-2]
39 Noman MZ,Janji B,Berchem G,Chouaib S.miR-210 and hypoxic microvesicles:Two critical components of hypoxia involved in the regulation of killer cells function.Cancer Lett2016;380:257-262[PMID:26523672 DOI:10.1016/j.canlet.2015.10.026]
40 Berchem G,Noman MZ,Bosseler M,Paggetti J,Baconnais S,Le Cam E,Nanbakhsh A,Moussay E,Mami-Chouaib F,Janji B,Chouaib S.Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-βand miR23a transfer.Oncoimmunology2016;5:e1062968[PMID:27141372 DOI:10.1080/2162402X.2015.1062968]
41 Sceneay J,Chow MT,Chen A,Halse HM,Wong CS,Andrews DM,Sloan EK,Parker BS,Bowtell DD,Smyth MJ,Moller A.Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche.Cancer Res 2012;72:3906-3911[PMID:22751463 DOI:10.1158/0008-5472.CAN-11-3873]
42 Baginska J,Viry E,Berchem G,Poli A,Noman MZ,van Moer K,Medves S,Zimmer J,Oudin A,Niclou SP,Bleackley RC,Goping IS,Chouaib S,Janji B.Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia.Proc Natl Acad Sci USA 2013;110:17450-17455[PMID:24101526 DOI:10.1073/pnas.1304790110]
43 Zhang J,Han C,Dai H,Hou J,Dong Y,Cui X,Xu L,Zhang M,Xia Q.Hypoxia-Inducible Factor-2αLimits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury.J Am Soc Nephrol2016;27:92-106[PMID:25956511 DOI:10.1681/ASN.2014121248]
44 Sarkar S,Germeraad WT,Rouschop KM,Steeghs EM,van Gelder M,Bos GM,Wieten L.Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells.PLoS One 2013;8:e64835[PMID:23724099 DOI:10.1371/journal.pone.0064835]
45 Chen J,Jiang CC,Jin L,Zhang XD.Regulation of PD-L1:a novel role of pro-survival signalling in cancer.Ann Oncol 2016;27:409-416[PMID:26681673 DOI:10.1093/annonc/mdv615]
46 Clambey ET,McNamee EN,Westrich JA,Glover LE,Campbell EL,Jedlicka P,de Zoeten EF,Cambier JC,Stenmark KR,Colgan SP,Eltzschig HK.Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa.Proc Natl Acad Sci USA2012;109:E2784-E2793[PMID:22988108 DOI:10.1073/pnas.1202366109]
47 Dang EV,Barbi J,Yang HY,Jinasena D,Yu H,Zheng Y,Bordman Z,Fu J,Kim Y,Yen HR,Luo W,Zeller K,Shimoda L,Topalian SL,Semenza GL,Dang CV,Pardoll DM,Pan F.Control of T(H)17/T(reg)balance by hypoxia-inducible factor 1.Cell2011;146:772-784[PMID:21871655 DOI:10.1016/j.cell.2011.07.033]
48 Obermajer N,Popp FC,Soeder Y,Haarer J,Geissler EK,Schlitt HJ,Dahlke MH.Conversion of Th17 into IL-17A(neg)regulatory T cells:a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy.JImmunol 2014;193:4988-4999[PMID:25305313DOI:10.4049/jimmunol.1401776]
49 Facciabene A,Peng X,Hagemann IS,Balint K,Barchetti A,Wang LP,Gimotty PA,Gilks CB,Lal P,Zhang L,Coukos G.Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg)cells.Nature 2011;475:226-230[PMID:21753853DOI:10.1038/nature10169]
50 Rhee I.Diverse macrophages polarization in tumor microenvironment.Arch Pharm Res 2016;39:1588-1596[PMID:27562774 DOI:10.1007/s12272-016-0820-y]
51 Obermajer N,Muthuswamy R,Lesnock J,Edwards RP,Kalinski P.Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells.Blood2011;118:5498-5505[PMID:21972293 DOI:10.1182/blood-2011-07-365825]
52 Juhas U,Ryba-Stanislawowska M,Szargiej P,Mysliwska J.Different pathways of macrophage activation and polarization.Postepy Hig Med Dosw(Online)2015;69:496-502[PMID:25983288 DOI:10.5604/17322693.1150133]
53 Doedens AL,Stockmann C,Rubinstein MP,Liao D,Zhang N,DeNardo DG,Coussens LM,Karin M,Goldrath AW,Johnson RS.Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.Cancer Res 2010;70:7465-7475[PMID:20841473 DOI:10.1158/0008-5472.CAN-10-1439]
54 Powell WC,Fingleton B,Wilson CL,Boothby M,Matrisian LM.The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis.Curr Biol1999;9:1441-1447[PMID:10607586 DOI:10.1016/S0960-9822(00)80113-X]
55 Hasmim M,Noman MZ,Messai Y,Bordereaux D,Gros G,Baud V,Chouaib S.Cutting edge:Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-β1.J Immunol 2013;191:5802-5806[PMID:24227785 DOI:10.4049/jimmunol.1302140]
56 Asgari Y,Zabihinpour Z,Salehzadeh-Yazdi A,Schreiber F,Masoudi-Nejad A.Alterations in cancer cell metabolism:the Warburg effect and metabolic adaptation.Genomics 2015;105:275-281[PMID:25773945 DOI:10.1016/j.ygeno.2015.03.001]
57 Duraiswamy J,Kaluza KM,Freeman GJ,Coukos G.Dual blockade of PD-1 and CTLA-4combined with tumor vaccine effectively restores T-cell rejection function in tumors.Cancer Res2013;73:3591-3603[PMID:23633484 DOI:10.1158/0008-5472.CAN-12-4100]
58 Larkin J,Chiarion-Sileni V,Gonzalez R,Grob JJ,Cowey CL,Lao CD,Schadendorf D,Dummer R,Smylie M,Rutkowski P,Ferrucci PF,Hill A,Wagstaff J,Carlino MS,Haanen JB,Maio M,Marquez-Rodas I,McArthur GA,Ascierto PA,Long GV,Callahan MK,Postow MA,Grossmann K,Sznol M,Dreno B,Bastholt L,Yang A,Rollin LM,Horak C,Hodi FS,Wolchok JD.Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.N Engl J Med 2015;373:23-34[PMID:26027431 DOI:10.1056/NEJMoa1504030]
59 Kwon ED,Drake CG,Scher HI,Fizazi K,Bossi A,van den Eertwegh AJ,Krainer M,Houede N,Santos R,Mahammedi H,Ng S,Maio M,Franke FA,Sundar S,Agarwal N,Bergman AM,Ciuleanu TE,Korbenfeld E,Sengel鴙L,Hansen S,Logothetis C,Beer TM,McHenry MB,Gagnier P,Liu D,Gerritsen WR.Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy(CA184-043):a multicentre,randomised,double-blind,phase 3 trial.Lancet Oncol 2014;15:700-712[PMID:24831977 DOI:10.1016/S1470-2045(14)70189-5]
60 Yang YL,Chu JY,Wang MR.Tumor genetic heterogeneity.Yi Chuan 2013;35:1-9[PMID:23357259 DOI:10.3724/SP.J.1005.2013.00001]
61 Erapaneedi R,Belousov VV,Schafers M,Kiefer F.A novel family of fluorescent hypoxia sensors reveal strong heterogeneity in tumor hypoxia at the cellular level.EMBO J 2016;35:102-113[PMID:26598532 DOI:10.15252/embj.201592775]
62 Peng G,Liu Y.Hypoxia-inducible factors in cancer stem cells and inflammation.Trends Pharmacol Sci 2015;36:374-383[PMID:25857287DOI:10.1016/j.tips.2015.03.003]
63 Jogi A,Ora I,Nilsson H,Lindeheim A,Makino Y,Poellinger L,Axelson H,Pahlman S.Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crestlike phenotype.Proc Natl Acad Sci USA 2002;99:7021-7026[PMID:12011461 DOI:10.1073/pnas.102660199]
64 McCord AM,Jamal M,Shankavaram UT,Lang FF,Camphausen K,Tofilon PJ.Physiologic oxygen concentration enhances the stem-like properties of CD133+human glioblastoma cells in vitro.Mol Cancer Res 2009;7:489-497[PMID:19372578 DOI:10.1158/1541-7786.MCR-08-0360]
65 Chen Y,De Marco MA,Graziani I,Gazdar AF,Strack PR,Miele L,Bocchetta M.Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung.Cancer Res 2007;67:7954-7959[PMID:17804701 DOI:10.1158/0008-5472.CAN-07-1229]
66 Morrison SJ,Perez SE,Qiao Z,Verdi JM,Hicks C,Weinmaster G,Anderson DJ.Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells.Cell 2000;101:499-510[PMID:10850492DOI:10.1016/S0092-8674(00)80860-0]
67 Li Z,Bao S,Wu Q,Wang H,Eyler C,Sathornsumetee S,Shi Q,Cao Y,Lathia J,McLendon RE,Hjelmeland AB,Rich JN.Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.Cancer Cell 2009;15:501-513[PMID:19477429 DOI:10.1016/j.ccr.2009.03.018]
68 Yeung TM,Gandhi SC,Bodmer WF.Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells.Proc Natl Acad Sci USA 2011;108:4382-4387[PMID:21368208 DOI:10.1073/pnas.1014519107]
69 Quail DF,Joyce JA.Microenvironmental regulation of tumor progression and metastasis.Nat Med 2013;19:1423-1437[PMID:24202395DOI:10.1038/nm.3394]
70 Song L,Yang MC,Knoff J,Sun ZY,Wu TC,Hung CF.Cancer immunotherapy using a potent immunodominant CTL epitope.Vaccine 2014;32:6039-6048[PMID:25245934 DOI:10.1016/j.vaccine.2014.09.021]
71 Noman MZ,Buart S,Van Pelt J,Richon C,Hasmim M,Leleu N,Suchorska WM,Jalil A,Lecluse Y,El Hage F,Giuliani M,Pichon C,Azzarone B,Mazure N,Romero P,Mami-Chouaib F,Chouaib S.The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis.J Immunol 2009;182:3510-3521[PMID:19265129 DOI:10.4049/jimmunol.0800854]
72 Barsoum IB,Hamilton TK,Li X,Cotechini T,Miles EA,Siemens DR,Graham CH.Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10:role of nitric oxide.Cancer Res 2011;71:7433-7441[PMID:22006996 DOI:10.1158/0008-5472.CAN-11-2104]
73 Noman MZ,Janji B,Kaminska B,Van Moer K,Pierson S,Przanowski P,Buart S,Berchem G,Romero P,Mami-Chouaib F,Chouaib S.Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.Cancer Res 2011;71:5976-5986[PMID:21810913DOI:10.1158/0008-5472.CAN-11-1094]
74 Noman MZ,Janji B,Berchem G,Mami-Chouaib F,Chouaib S.Hypoxia-induced autophagy:a new player in cancer immunotherapy?Autophagy2012;8:704-706[PMID:22441015 DOI:10.4161/auto.19572]
75 Viry E,Baginska J,Berchem G,Noman MZ,Medves S,Chouaib S,Janji B.Autophagic degradation of GZMB/granzyme B:a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis.Autophagy 2014;10:173-175[PMID:24248158DOI:10.4161/auto.26924]
76 Noman MZ,Buart S,Romero P,Ketari S,Janji B,Mari B,Mami-Chouaib F,Chouaib S.Hypoxiainducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells.Cancer Res 2012;72:4629-4641[PMID:22962263 DOI:10.1158/0008-5472.CAN-12-1383]
77 Perier A,Fregni G,Wittnebel S,Gad S,Allard M,Gervois N,Escudier B,Azzarone B,Caignard A.Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma.Oncogene 2011;30:2622-2632[PMID:21258414 DOI:10.1038/onc.2010.638]
78 Messai Y,Noman MZ,Janji B,Hasmim M,Escudier B,Chouaib S.The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing.Autophagy 2015 Feb 25.[Epub ahead of print][PMID:25714778 DOI:10.1080/15548627.2015.1017194]
79 Barar J,Omidi Y.Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy.Bioimpacts 2013;3:149-162[PMID:24455478 DOI:10.5681/bi.2013.036]
80 Shi Q,Maas L,Veith C,Van Schooten FJ,Godschalk RW.Acidic cellular microenvironment modifies carcinogen-induced DNA damage and repair.Arch Toxicol 2016;91:2425-2441[PMID:28005143 DOI:10.1007/s00204-016-1907-4]
81 Lardner A.The effects of extracellular pH on immune function.J Leukoc Biol 2001;69:522-530[PMID:11310837]
82 Nakagawa Y,Negishi Y,Shimizu M,Takahashi M,Ichikawa M,Takahashi H.Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes.Immunol Lett 2015;167:72-86[PMID:26209187DOI:10.1016/j.imlet.2015.07.003]
83 Payen VL,Porporato PE,Baselet B,Sonveaux P.Metabolic changes associated with tumor metastasis,part 1:tumor pH,glycolysis and the pentose phosphate pathway.Cell Mol Life Sci 2016;73:1333-1348[PMID:26626411 DOI:10.1007/s00018-015-2098-5]
84 Bental M,Deutsch C.An NMR view of primary T-lymphocyte activation.NMR in Physiology and Medicine(RJ Gillies,ed)NY,Chapter 18:Academic Press,1994
85 Bellone M,Calcinotto A.Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes.Front Oncol2013;3:231[PMID:24062984 DOI:10.3389/fonc.2013.00231]
86 Damaghi M,Tafreshi NK,Lloyd MC,Sprung R,Estrella V,Wojtkowiak JW,Morse DL,Koomen JM,Bui MM,Gatenby RA,Gillies RJ.Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane.Nat Commun 2015;6:8752[PMID:26658462 DOI:10.1038/ncomms9752]
87 Okajima F.Regulation of inflammation by extracellular acidification and proton-sensing GPCRs.Cell Signal 2013;25:2263-2271[PMID:23917207 DOI:10.1016/j.cellsig.2013.07.022]
88 Cairns R,Papandreou I,Denko N.Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment.Mol Cancer Res 2006;4:61-70[PMID:16513837 DOI:10.1158/1541-7786.MCR-06-0002]
89 Wang W,Singh S,Zeng DL,King K,Nema S.Antibody structure,instability,and formulation.J Pharm Sci 2007;96:1-26[PMID:16998873 DOI:10.1002/jps.20727]
90 Pilon-Thomas S,Kodumudi KN,El-Kenawi AE,Russell S,Weber AM,Luddy K,Damaghi M,Wojtkowiak JW,MuléJJ,Ibrahim-Hashim A,Gillies RJ.Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.Cancer Res 2016;76:1381-1390[PMID:26719539 DOI:10.1158/0008-5472.CAN-15-1743]
2 Klein G,Sjogren HO,Klein E,Hellstrom KE.Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host.Cancer Res 1960;20:1561-1572[PMID:13756652]
3 Burnet FM.Immunological aspects of malignant disease.Lancet 1967;1:1171-1174[PMID:4165129DOI:10.1016/S0140-6736(67)92837-1]
4 Mellman I,Coukos G,Dranoff G.Cancer immunotherapy comes of age.Nature 2011;480:480-489[PMID:22193102 DOI:10.1038/nature10673]
5 Melero I,Gaudernack G,Gerritsen W,Huber C,Parmiani G,Scholl S,Thatcher N,Wagstaff J,Zielinski C,Faulkner I,Mellstedt H.Therapeutic vaccines for cancer:an overview of clinical trials.Nat Rev Clin Oncol 2014;11:509-524[PMID:25001465 DOI:10.1038/nrclinonc.2014.111]
6 McNutt M.Cancer immunotherapy.Science2013;342:1417[PMID:24357273 DOI:10.1126/science.1249481]
7 Immunotherapy:combine and conquer.Nat Med2015;21:415[PMID:25951522 DOI:10.1038/nm.3865]
8 Sharma P,Allison JP.The future of immune checkpoint therapy.Science 2015;348:56-61[PMID:25838373 DOI:10.1126/science.aaa8172]
9 Lee DW,Kochenderfer JN,Stetler-Stevenson M,Cui YK,Delbrook C,Feldman SA,Fry TJ,Orentas R,Sabatino M,Shah NN,Steinberg SM,Stroncek D,Tschernia N,Yuan C,Zhang H,Zhang L,Rosenberg SA,Wayne AS,Mackall CL.T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults:a phase 1 dose-escalation trial.Lancet 2015;385:517-528[PMID:25319501 DOI:10.1016/S0140-6736(14)61403-3]
10 Turtle CJ,Hanafi LA,Berger C,Gooley TA,Cherian S,Hudecek M,Sommermeyer D,Melville K,Pender B,Budiarto TM,Robinson E,Steevens NN,Chaney C,Soma L,Chen X,Yeung C,Wood B,Li D,Cao J,Heimfeld S,Jensen MC,Riddell SR,Maloney DG.CD19 CAR-T cells of defined CD4+:CD8+composition in adult B cell ALL patients.JClin Invest 2016;126:2123-2138[PMID:27111235DOI:10.1172/JCI85309]
11 Topalian SL,Hodi FS,Brahmer JR,Gettinger SN,Smith DC,McDermott DF,Powderly JD,Carvajal RD,Sosman JA,Atkins MB,Leming PD,Spigel DR,Antonia SJ,Horn L,Drake CG,Pardoll DM,Chen L,Sharfman WH,Anders RA,Taube JM,McMiller TL,Xu H,Korman AJ,Jure-Kunkel M,Agrawal S,McDonald D,Kollia GD,Gupta A,Wigginton JM,Sznol M.Safety,activity,and immune correlates of antiPD-1 antibody in cancer.N Engl J Med 2012;366:2443-2454[PMID:22658127 DOI:10.1056/NEJMoa1200690]
12 Noman MZ,Messai Y,CarréT,Akalay I,Méron M,Janji B,Hasmim M,Chouaib S.Microenvironmental hypoxia orchestrating the cell stroma cross talk,tumor progression and antitumor response.Crit Rev Immunol 2011;31:357-377[PMID:22142164 DOI:10.1615/CritRevImmunol.v31.i5.10]
13 Klemm F,Joyce JA.Microenvironmental regulation of therapeutic response in cancer.Trends Cell Biol 2015;25:198-213[PMID:25540894DOI:10.1016/j.tcb.2014.11.006]
14 Nagelkerke A,Bussink J,Rowan AE,Span PN.The mechanical microenvironment in cancer:How physics affects tumours.Semin Cancer Biol2015;35:62-70[PMID:26343578 DOI:10.1016/j.semcancer.2015.09.001]
15 Marchiq I,Pouysségur J.Hypoxia,cancer metabolism and the therapeutic benefit of targeting lactate/H(+)symporters.J Mol Med(Berl)2016;94:155-171[PMID:26099350 DOI:10.1007/s00109-015-1307-x]
16 Pastorek J,Pastorekova S.Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy:from biology to clinical use.Semin Cancer Biol 2015;31:52-64[PMID:25117006 DOI:10.1016/j.semcancer.2014.08.002]
17 Barsoum IB,Smallwood CA,Siemens DR,Graham CH.A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.Cancer Res 2014;74:665-674[PMID:24336068DOI:10.1158/0008-5472.can-13-0992]
18 Noman MZ,Hasmim M,Messai Y,Terry S,Kieda C,Janji B,Chouaib S.Hypoxia:a key player in antitumor immune response.A Review in the Theme:Cellular Responses to Hypoxia.Am JPhysiol Cell Physiol 2015;309:C569-C579[PMID:26310815 DOI:10.1152/ajpcell.00207.2015]
19 Semenza GL.Hypoxia-inducible factors in physiology and medicine.Cell 2012;148:399-408[PMID:22304911 DOI:10.1016/j.cell.2012.01.021]
20 Thiel M,Chouker A,Ohta A,Jackson E,Caldwell C,Smith P,Lukashev D,Bittmann I,Sitkovsky MV.Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury.PLoSBiol 2005;3:e174[PMID:15857155 DOI:10.1371/journal.pbio.0030174]
21 Nakamura H,Makino Y,Okamoto K,Poellinger L,Ohnuma K,Morimoto C,Tanaka H.TCRengagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycinsensitive pathway under hypoxic conditions in human peripheral T cells.J Immunol 2005;174:7592-7599[PMID:15944259 DOI:10.4049/jimmunol.174.12.7592]
22 Tao JH,Barbi J,Pan F.Hypoxia-inducible factors in T lymphocyte differentiation and function.A Review in the Theme:Cellular Responses to Hypoxia.Am J Physiol Cell Physiol 2015;309:C580-C589[PMID:26354751 DOI:10.1152/ajpcell.00204.2015]
23 Phan AT,Goldrath AW.Hypoxia-inducible factors regulate T cell metabolism and function.Mol Immunol 2015;68:527-535[PMID:26298577DOI:10.1016/j.molimm.2015.08.004]
24 Doedens AL,Phan AT,Stradner MH,Fujimoto JK,Nguyen JV,Yang E,Johnson RS,Goldrath AW.Hypoxia-inducible factors enhance the effector responses of CD8(+)T cells to persistent antigen.Nat Immunol 2013;14:1173-1182[PMID:24076634 DOI:10.1038/ni.2714]
25 Finlay DK,Rosenzweig E,Sinclair LV,FeijooCarnero C,Hukelmann JL,Rolf J,Panteleyev AA,Okkenhaug K,Cantrell DA.PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+T cells.J Exp Med 2012;209:2441-2453[PMID:23183047 DOI:10.1084/jem.20112607]
26 Jiménez-Pérez L,Cidad P,álvarez-Miguel I,Santos-Hipólito A,Torres-Merino R,Alonso E,de la Fuente Má,López-López JR,Pérez-García MT.Molecular Determinants of Kv1.3 Potassium Channels-induced Proliferation.J Biol Chem 2016;291:3569-3580[PMID:26655221 DOI:10.1074/jbc.M115.678995]
27 Lukashev D,Klebanov B,Kojima H,Grinberg A,Ohta A,Berenfeld L,Wenger RH,Ohta A,Sitkovsky M.Cutting edge:hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+and CD8+T lymphocytes.J Immunol 2006;177:4962-4965[PMID:17015677 DOI:10.4049/jimmunol.177.8.4962]
28 Hoskin DW,Mader JS,Furlong SJ,Conrad DM,Blay J.Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells(Review).Int JOncol 2008;32:527-535[PMID:18292929 DOI:10.3892/ijo.32.3.527]
29 Deaglio S,Dwyer KM,Gao W,Friedman D,Usheva A,Erat A,Chen JF,Enjyoji K,Linden J,Oukka M,Kuchroo VK,Strom TB,Robson SC.Adenosine generation catalyzed by CD39and CD73 expressed on regulatory T cells mediates immune suppression.J Exp Med 2007;204:1257-1265[PMID:17502665 DOI:10.1084/jem.20062512]
30 Tan S,Bose R,Derrick M.Hypoxia-ischemia in fetal rabbit brain increases reactive nitrogen species production:quantitative estimation of nitrotyrosine.Free Radic Biol Med 2001;30:1045-1051[PMID:11316585 DOI:10.1016/S0891-5849(01)00499-3]
31 Nagaraj S,Gupta K,Pisarev V,Kinarsky L,Sherman S,Kang L,Herber DL,Schneck J,Gabrilovich DI.Altered recognition of antigen is a mechanism of CD8+T cell tolerance in cancer.Nat Med 2007;13:828-835[PMID:17603493 DOI:10.1038/nm1609]
32 Noman MZ,Chouaib S.Targeting hypoxia at the forefront of anticancer immune responses.Oncoimmunology 2014;3:e954463[PMID:25964858DOI:10.4161/21624011.2014.954463]
33 Noman MZ,Desantis G,Janji B,Hasmim M,Karray S,Dessen P,Bronte V,Chouaib S.PD-L1is a novel direct target of HIF-1α,and its blockade under hypoxia enhanced MDSC-mediated T cell activation.J Exp Med 2014;211:781-790[PMID:24778419 DOI:10.1084/jem.20131916]
34 Palazón A,Martínez-Forero I,Teijeira A,MoralesKastresana A,Alfaro C,Sanmamed MF,PerezGracia JL,Pe駏elas I,Hervás-Stubbs S,Rouzaut A,de Landázuri MO,Jure-Kunkel M,Aragonés J,Melero I.The HIF-1αhypoxia response in tumorinfiltrating T lymphocytes induces functional CD137(4-1BB)for immunotherapy.Cancer Discov 2012;2:608-623[PMID:22719018 DOI:10.1158/2159-8290.CD-11-0314]
35 Weigelin B,Bolanos E,Rodriguez-Ruiz ME,Martinez-Forero I,Friedl P,Melero I.AntiCD137 monoclonal antibodies and adoptive Tcell therapy:a perfect marriage?Cancer Immunol Immunother 2016;65:493-497[PMID:26970765DOI:10.1007/s00262-016-1818-5]
36 Muntasell A,Ochoa MC,Cordeiro L,Berraondo P,López-Díaz de Cerio A,Cabo M,López-Botet M,Melero I.Targeting NK-cell checkpoints for cancer immunotherapy.Curr Opin Immunol2017;45:73-81[PMID:28236750 DOI:10.1016/j.coi.2017.01.003]
37 Yamada N,Yamanegi K,Ohyama H,Hata M,Nakasho K,Futani H,Okamura H,Terada N.Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICAin osteosarcoma cells in a HIF-1α-dependent manner.Int J Oncol 2012;41:2005-2012[PMID:22992985 DOI:10.3892/ijo.2012.1630]
38 Abruzzese MP,Bilotta MT,Fionda C,Zingoni A,Soriani A,Vulpis E,Borrelli C,Zitti B,Petrucci MT,Ricciardi MR,Molfetta R,Paolini R,Santoni A,Cippitelli M.Inhibition of bromodomain and extra-terminal(BET)proteins increases NKG2Dligand MICA expression and sensitivity to NKcell-mediated cytotoxicity in multiple myeloma cells:role of cMYC-IRF4-miR-125b interplay.JHematol Oncol 2016;9:134[PMID:27903272 DOI:10.1186/s13045-016-0362-2]
39 Noman MZ,Janji B,Berchem G,Chouaib S.miR-210 and hypoxic microvesicles:Two critical components of hypoxia involved in the regulation of killer cells function.Cancer Lett2016;380:257-262[PMID:26523672 DOI:10.1016/j.canlet.2015.10.026]
40 Berchem G,Noman MZ,Bosseler M,Paggetti J,Baconnais S,Le Cam E,Nanbakhsh A,Moussay E,Mami-Chouaib F,Janji B,Chouaib S.Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-βand miR23a transfer.Oncoimmunology2016;5:e1062968[PMID:27141372 DOI:10.1080/2162402X.2015.1062968]
41 Sceneay J,Chow MT,Chen A,Halse HM,Wong CS,Andrews DM,Sloan EK,Parker BS,Bowtell DD,Smyth MJ,Moller A.Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche.Cancer Res 2012;72:3906-3911[PMID:22751463 DOI:10.1158/0008-5472.CAN-11-3873]
42 Baginska J,Viry E,Berchem G,Poli A,Noman MZ,van Moer K,Medves S,Zimmer J,Oudin A,Niclou SP,Bleackley RC,Goping IS,Chouaib S,Janji B.Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia.Proc Natl Acad Sci USA 2013;110:17450-17455[PMID:24101526 DOI:10.1073/pnas.1304790110]
43 Zhang J,Han C,Dai H,Hou J,Dong Y,Cui X,Xu L,Zhang M,Xia Q.Hypoxia-Inducible Factor-2αLimits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury.J Am Soc Nephrol2016;27:92-106[PMID:25956511 DOI:10.1681/ASN.2014121248]
44 Sarkar S,Germeraad WT,Rouschop KM,Steeghs EM,van Gelder M,Bos GM,Wieten L.Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells.PLoS One 2013;8:e64835[PMID:23724099 DOI:10.1371/journal.pone.0064835]
45 Chen J,Jiang CC,Jin L,Zhang XD.Regulation of PD-L1:a novel role of pro-survival signalling in cancer.Ann Oncol 2016;27:409-416[PMID:26681673 DOI:10.1093/annonc/mdv615]
46 Clambey ET,McNamee EN,Westrich JA,Glover LE,Campbell EL,Jedlicka P,de Zoeten EF,Cambier JC,Stenmark KR,Colgan SP,Eltzschig HK.Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa.Proc Natl Acad Sci USA2012;109:E2784-E2793[PMID:22988108 DOI:10.1073/pnas.1202366109]
47 Dang EV,Barbi J,Yang HY,Jinasena D,Yu H,Zheng Y,Bordman Z,Fu J,Kim Y,Yen HR,Luo W,Zeller K,Shimoda L,Topalian SL,Semenza GL,Dang CV,Pardoll DM,Pan F.Control of T(H)17/T(reg)balance by hypoxia-inducible factor 1.Cell2011;146:772-784[PMID:21871655 DOI:10.1016/j.cell.2011.07.033]
48 Obermajer N,Popp FC,Soeder Y,Haarer J,Geissler EK,Schlitt HJ,Dahlke MH.Conversion of Th17 into IL-17A(neg)regulatory T cells:a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy.JImmunol 2014;193:4988-4999[PMID:25305313DOI:10.4049/jimmunol.1401776]
49 Facciabene A,Peng X,Hagemann IS,Balint K,Barchetti A,Wang LP,Gimotty PA,Gilks CB,Lal P,Zhang L,Coukos G.Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg)cells.Nature 2011;475:226-230[PMID:21753853DOI:10.1038/nature10169]
50 Rhee I.Diverse macrophages polarization in tumor microenvironment.Arch Pharm Res 2016;39:1588-1596[PMID:27562774 DOI:10.1007/s12272-016-0820-y]
51 Obermajer N,Muthuswamy R,Lesnock J,Edwards RP,Kalinski P.Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells.Blood2011;118:5498-5505[PMID:21972293 DOI:10.1182/blood-2011-07-365825]
52 Juhas U,Ryba-Stanislawowska M,Szargiej P,Mysliwska J.Different pathways of macrophage activation and polarization.Postepy Hig Med Dosw(Online)2015;69:496-502[PMID:25983288 DOI:10.5604/17322693.1150133]
53 Doedens AL,Stockmann C,Rubinstein MP,Liao D,Zhang N,DeNardo DG,Coussens LM,Karin M,Goldrath AW,Johnson RS.Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.Cancer Res 2010;70:7465-7475[PMID:20841473 DOI:10.1158/0008-5472.CAN-10-1439]
54 Powell WC,Fingleton B,Wilson CL,Boothby M,Matrisian LM.The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis.Curr Biol1999;9:1441-1447[PMID:10607586 DOI:10.1016/S0960-9822(00)80113-X]
55 Hasmim M,Noman MZ,Messai Y,Bordereaux D,Gros G,Baud V,Chouaib S.Cutting edge:Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-β1.J Immunol 2013;191:5802-5806[PMID:24227785 DOI:10.4049/jimmunol.1302140]
56 Asgari Y,Zabihinpour Z,Salehzadeh-Yazdi A,Schreiber F,Masoudi-Nejad A.Alterations in cancer cell metabolism:the Warburg effect and metabolic adaptation.Genomics 2015;105:275-281[PMID:25773945 DOI:10.1016/j.ygeno.2015.03.001]
57 Duraiswamy J,Kaluza KM,Freeman GJ,Coukos G.Dual blockade of PD-1 and CTLA-4combined with tumor vaccine effectively restores T-cell rejection function in tumors.Cancer Res2013;73:3591-3603[PMID:23633484 DOI:10.1158/0008-5472.CAN-12-4100]
58 Larkin J,Chiarion-Sileni V,Gonzalez R,Grob JJ,Cowey CL,Lao CD,Schadendorf D,Dummer R,Smylie M,Rutkowski P,Ferrucci PF,Hill A,Wagstaff J,Carlino MS,Haanen JB,Maio M,Marquez-Rodas I,McArthur GA,Ascierto PA,Long GV,Callahan MK,Postow MA,Grossmann K,Sznol M,Dreno B,Bastholt L,Yang A,Rollin LM,Horak C,Hodi FS,Wolchok JD.Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.N Engl J Med 2015;373:23-34[PMID:26027431 DOI:10.1056/NEJMoa1504030]
59 Kwon ED,Drake CG,Scher HI,Fizazi K,Bossi A,van den Eertwegh AJ,Krainer M,Houede N,Santos R,Mahammedi H,Ng S,Maio M,Franke FA,Sundar S,Agarwal N,Bergman AM,Ciuleanu TE,Korbenfeld E,Sengel鴙L,Hansen S,Logothetis C,Beer TM,McHenry MB,Gagnier P,Liu D,Gerritsen WR.Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy(CA184-043):a multicentre,randomised,double-blind,phase 3 trial.Lancet Oncol 2014;15:700-712[PMID:24831977 DOI:10.1016/S1470-2045(14)70189-5]
60 Yang YL,Chu JY,Wang MR.Tumor genetic heterogeneity.Yi Chuan 2013;35:1-9[PMID:23357259 DOI:10.3724/SP.J.1005.2013.00001]
61 Erapaneedi R,Belousov VV,Schafers M,Kiefer F.A novel family of fluorescent hypoxia sensors reveal strong heterogeneity in tumor hypoxia at the cellular level.EMBO J 2016;35:102-113[PMID:26598532 DOI:10.15252/embj.201592775]
62 Peng G,Liu Y.Hypoxia-inducible factors in cancer stem cells and inflammation.Trends Pharmacol Sci 2015;36:374-383[PMID:25857287DOI:10.1016/j.tips.2015.03.003]
63 Jogi A,Ora I,Nilsson H,Lindeheim A,Makino Y,Poellinger L,Axelson H,Pahlman S.Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crestlike phenotype.Proc Natl Acad Sci USA 2002;99:7021-7026[PMID:12011461 DOI:10.1073/pnas.102660199]
64 McCord AM,Jamal M,Shankavaram UT,Lang FF,Camphausen K,Tofilon PJ.Physiologic oxygen concentration enhances the stem-like properties of CD133+human glioblastoma cells in vitro.Mol Cancer Res 2009;7:489-497[PMID:19372578 DOI:10.1158/1541-7786.MCR-08-0360]
65 Chen Y,De Marco MA,Graziani I,Gazdar AF,Strack PR,Miele L,Bocchetta M.Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung.Cancer Res 2007;67:7954-7959[PMID:17804701 DOI:10.1158/0008-5472.CAN-07-1229]
66 Morrison SJ,Perez SE,Qiao Z,Verdi JM,Hicks C,Weinmaster G,Anderson DJ.Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells.Cell 2000;101:499-510[PMID:10850492DOI:10.1016/S0092-8674(00)80860-0]
67 Li Z,Bao S,Wu Q,Wang H,Eyler C,Sathornsumetee S,Shi Q,Cao Y,Lathia J,McLendon RE,Hjelmeland AB,Rich JN.Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.Cancer Cell 2009;15:501-513[PMID:19477429 DOI:10.1016/j.ccr.2009.03.018]
68 Yeung TM,Gandhi SC,Bodmer WF.Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells.Proc Natl Acad Sci USA 2011;108:4382-4387[PMID:21368208 DOI:10.1073/pnas.1014519107]
69 Quail DF,Joyce JA.Microenvironmental regulation of tumor progression and metastasis.Nat Med 2013;19:1423-1437[PMID:24202395DOI:10.1038/nm.3394]
70 Song L,Yang MC,Knoff J,Sun ZY,Wu TC,Hung CF.Cancer immunotherapy using a potent immunodominant CTL epitope.Vaccine 2014;32:6039-6048[PMID:25245934 DOI:10.1016/j.vaccine.2014.09.021]
71 Noman MZ,Buart S,Van Pelt J,Richon C,Hasmim M,Leleu N,Suchorska WM,Jalil A,Lecluse Y,El Hage F,Giuliani M,Pichon C,Azzarone B,Mazure N,Romero P,Mami-Chouaib F,Chouaib S.The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis.J Immunol 2009;182:3510-3521[PMID:19265129 DOI:10.4049/jimmunol.0800854]
72 Barsoum IB,Hamilton TK,Li X,Cotechini T,Miles EA,Siemens DR,Graham CH.Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10:role of nitric oxide.Cancer Res 2011;71:7433-7441[PMID:22006996 DOI:10.1158/0008-5472.CAN-11-2104]
73 Noman MZ,Janji B,Kaminska B,Van Moer K,Pierson S,Przanowski P,Buart S,Berchem G,Romero P,Mami-Chouaib F,Chouaib S.Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.Cancer Res 2011;71:5976-5986[PMID:21810913DOI:10.1158/0008-5472.CAN-11-1094]
74 Noman MZ,Janji B,Berchem G,Mami-Chouaib F,Chouaib S.Hypoxia-induced autophagy:a new player in cancer immunotherapy?Autophagy2012;8:704-706[PMID:22441015 DOI:10.4161/auto.19572]
75 Viry E,Baginska J,Berchem G,Noman MZ,Medves S,Chouaib S,Janji B.Autophagic degradation of GZMB/granzyme B:a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis.Autophagy 2014;10:173-175[PMID:24248158DOI:10.4161/auto.26924]
76 Noman MZ,Buart S,Romero P,Ketari S,Janji B,Mari B,Mami-Chouaib F,Chouaib S.Hypoxiainducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells.Cancer Res 2012;72:4629-4641[PMID:22962263 DOI:10.1158/0008-5472.CAN-12-1383]
77 Perier A,Fregni G,Wittnebel S,Gad S,Allard M,Gervois N,Escudier B,Azzarone B,Caignard A.Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma.Oncogene 2011;30:2622-2632[PMID:21258414 DOI:10.1038/onc.2010.638]
78 Messai Y,Noman MZ,Janji B,Hasmim M,Escudier B,Chouaib S.The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing.Autophagy 2015 Feb 25.[Epub ahead of print][PMID:25714778 DOI:10.1080/15548627.2015.1017194]
79 Barar J,Omidi Y.Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy.Bioimpacts 2013;3:149-162[PMID:24455478 DOI:10.5681/bi.2013.036]
80 Shi Q,Maas L,Veith C,Van Schooten FJ,Godschalk RW.Acidic cellular microenvironment modifies carcinogen-induced DNA damage and repair.Arch Toxicol 2016;91:2425-2441[PMID:28005143 DOI:10.1007/s00204-016-1907-4]
81 Lardner A.The effects of extracellular pH on immune function.J Leukoc Biol 2001;69:522-530[PMID:11310837]
82 Nakagawa Y,Negishi Y,Shimizu M,Takahashi M,Ichikawa M,Takahashi H.Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes.Immunol Lett 2015;167:72-86[PMID:26209187DOI:10.1016/j.imlet.2015.07.003]
83 Payen VL,Porporato PE,Baselet B,Sonveaux P.Metabolic changes associated with tumor metastasis,part 1:tumor pH,glycolysis and the pentose phosphate pathway.Cell Mol Life Sci 2016;73:1333-1348[PMID:26626411 DOI:10.1007/s00018-015-2098-5]
84 Bental M,Deutsch C.An NMR view of primary T-lymphocyte activation.NMR in Physiology and Medicine(RJ Gillies,ed)NY,Chapter 18:Academic Press,1994
85 Bellone M,Calcinotto A.Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes.Front Oncol2013;3:231[PMID:24062984 DOI:10.3389/fonc.2013.00231]
86 Damaghi M,Tafreshi NK,Lloyd MC,Sprung R,Estrella V,Wojtkowiak JW,Morse DL,Koomen JM,Bui MM,Gatenby RA,Gillies RJ.Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane.Nat Commun 2015;6:8752[PMID:26658462 DOI:10.1038/ncomms9752]
87 Okajima F.Regulation of inflammation by extracellular acidification and proton-sensing GPCRs.Cell Signal 2013;25:2263-2271[PMID:23917207 DOI:10.1016/j.cellsig.2013.07.022]
88 Cairns R,Papandreou I,Denko N.Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment.Mol Cancer Res 2006;4:61-70[PMID:16513837 DOI:10.1158/1541-7786.MCR-06-0002]
89 Wang W,Singh S,Zeng DL,King K,Nema S.Antibody structure,instability,and formulation.J Pharm Sci 2007;96:1-26[PMID:16998873 DOI:10.1002/jps.20727]
90 Pilon-Thomas S,Kodumudi KN,El-Kenawi AE,Russell S,Weber AM,Luddy K,Damaghi M,Wojtkowiak JW,MuléJJ,Ibrahim-Hashim A,Gillies RJ.Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.Cancer Res 2016;76:1381-1390[PMID:26719539 DOI:10.1158/0008-5472.CAN-15-1743]