Effects of tumor immune microenvironment on conventional cancer therapies

Transcript

1 http / /www. biother. org Chin J Cancer Biother Jun Vol. 19 No. 3 DOI /j. issn X Mayo Clinic Johns Hopkins T 2005 T CD24 CD137 Treg CD8 + T HER2 /neu FcR + antibody-dependent cell-mediated cytotoxicity ADCC HER2 /neu Cancer Cell sdwang@ moon. ibp. ac. cn R R R A X Effects of tumor immune microenvironment on conventional cancer therapies WANG Sheng-dian JIA Ming-ming CAS Key Laboratory of Infection and Immunity Institute of Biophysics Chinese Academy of Sciences Beijing China Abstract The immune system can eliminate malignant cells or prevent tumor growth by recognizing and destroying malignant cells. Under the strong selective pressure from the host immune system malignant cells can rapidly acquire new phenotypes through high somatic mutations to evade immune surveillance. The selected tumor cell variants make use of all kinds of immunosuppressive mechanisms to establish an immunosuppressive microenvironment to resist and suppress antitumor immune response allowing the tumors expend and become clinically detectable. The current tumor therapies mainly focus on the direct inhibition of tumor cell proliferation as well as the killing and elimination of tumor cells. However the growing evidence suggests that the conventional tumor therapies can elicit specific cellular responses that render tumor-cell 973 No. 2012CB No Project supported by the Grant from the National Basic Research Development Program of China 973 Program No. 2012CB and the Major Research Plan of the National Natural Science Foundation of China No http / /www. cnki. net /kcms /detail / R html

2 death immunogenic which may activate the innate immune signaling pathways and then induce the intrinsic anti-tumor immune responses. This potential mechanism plays a key role in the therapeutic effects of the conventional anticancer treatments especially in preventing the recurrence of residual tumor cells. Here we intend to demonstrate the molecular and cellular mechanisms of the anti-tumor immune responses and the immunosuppressive tumor microenvironment in the process of tumor development and the conventional anticancer treatments especially focusing on their effects on the therapeutic effects of the conventional anticancer treatments. We also attempt to explore the rational therapeutic strategies targeting the components of tumor immune microenvironment which may shed light on the improvement of the current conventional anticancer therapies and the development of new anticancer treatments. Key words tumor immunosurveillance tumor therapy tumor microenvironment immune suppression Chin J Cancer Biother dormant Paul Ehrlich 50 Sir. Macfarlane Burnet Lewis Thomas tumor immunosur- veillance myeloid derived suppressor cell MDSC

3 . 231 danger signal NK γδt NKT NKG2D /CD1 abscopal effect IFN-γ IFN-γ CTL 3 IFN-γ 8 NO 1. 3 NK TRAIL IFN-γ IL-12 IL-12 NK IFN-γ IFN-γ IFN-γR1 IL-12 TNF-α 5 1 B 40% ~ 60% vs 0 ~ 6% 6 TRAIL FasL 3 CD4 + CD8 + T T CD4 + T IL-2 IL-21 IL-15 CD8 + T CD8 + T TCR IFN-γ Rag1 - / - Rag2 - / - SCID 3 Rag2 - / - 40% Rag2 - / - methyl- CD8 + T CD4 + T cholanthrene MCA 7 MCA 200 d 200 d CD4 + CD8 + T IFN-γ IL-12

4 % 11 TNF MCA 200 d TNF 4 T regulatory T cell Treg MDSC M2 2 tumor associated macrophage 1 ~ 2 TAM Treg 16 T homeostasis Treg Treg Treg MDSC 1% 4 ~ MDSC NK NKT CD4 + CD8 + T 18 TAM M MHC I TAP1 LMP2 LMP 7 CTL NKG2D NK Treg B7-H1 19 B7-H1 PD-L1T T T 20 Fas 2 FasL TGF-β IL-10 IDO VEGF T

5 CD4 + CD8 + T DC CD11c-DTR T IFN-γ IL-1β IFN-γ IL-1β IFN-γ IL-1β DC T CTL Obeid necrosis CRT IL-8 IL-10 TNF-α CRT DC HMGB1 DC apoptosis CRT sirna CRT DC C1q CRT phosphatidylserine PS calreticulin CRT CD DC DC DC DC MHC / T T DC DC Toll Toll-like recep- TLR pathogen asso- tors ciated molecular pattern PAMP 21 damage associated molecular pattern DAMP

6 Apetoh 25 TLR DC 2. 2 TLR DC TLR4 - / - MyD88 - / - DC DC 9 T 5 DC TLR4 / 3 MyD88 chronic lymphatic leukemia CLL DC TLR4 / CD52 acute myeloid leukemia HMGB1 MyD88 AML CD33 non- hodgkin s lymphoma NHL CLL CD20 X 4 / TLR4 HMGB1 25 Ghiringhelli 26 HER2 /neu CD8 + T HER2 /neu TLR4 - / - MyD88 - / - 3 epithelial growth TLR4 factor receptor EGFR EGFR HER2 /neu vascular endothelial growth factor VEGF 29 HER2 /neu TLR4 TLR4 Asp299Gly Asp299Gly HER2 /neu Nlrp3 - / - caspase-1 - / - Fc IL-1βR NK FcR antibody-dependent cell-mediated cytotoxicity ADCC ATP DC P2X7 DC NLRP3 FcR + caspase-1 IL-1β HMGB1 TLR CD8 + IL-1β IL-1β T HMGB1 CD8 + CD4 + CD8 + T Rag-1 - / - T B MyD88 - / - IL-1β IL-1βR HER2 /neu T HER2 /neu IL-1β Nlrp3 - / - caspase-1 - / - HER2 /neu ADCC T HMGB1 32 HER2 /neu DC MyD88 DC T MHC I HER2 /neu CD95 CTL HER2 /neu + T 28 HER2 /neu + T CpG 30 HER2 /neu

7 T CD20 T 33 HER2 /neu T 4-1BB CD137 CD40 PD-1 IL- 15R /IL-15 HER2 / neu CD8 + T CD8 + T CD8 + T 4-1BB 35 T 36 CD25 Treg 37

8 IL-2 / Treg T CTLA-4 T Treg CTLA-4 ipilimumab 2011 FDA 4 Ⅲ CTLA-4 gp 100 gp 100 gp CT- LA CTLA-4 gp CTLA-4 CD8 + T Treg 40 CTLA-4 CTLA-4 dacarbazine % 36. 3% % 17. 9% % 12. 2% 41 PD-1 T B7-H1 PD-L1 PD-1 T T B7-H1 /PD-1 B7-H1 PD-1 Ⅱ T T T T T T 1 Hanahan D Weinberg RA. Hallmarks of cancer The next gener- 44 ation J T and adaptive immunity to cancer J Cell Stutman O. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice J. Science Dunn GP Old LJ Schreiber RD. The three Es of cancer immunoediting J. Annu Rev Immunol Bancroft GJ Schreiber RD Unanue ER. Natural immunity A T-cell-independent pathway of macrophage activation defined in the SCID mouse J. Immunol Rev Vesely MD Kershaw MH Schreiber RD et al. Natural innate. Annu Rev Immunol Smyth MJ Thia KY Street SE et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma J. J

9 . 237 Exp Med Shankaran V Ikeda H Bruce AT et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumor immunogenicity J. Nature Galon J Costes A Sanchez-Cabo F et al. Type density and location of immune cells within human colorectal tumors predict clinical outcome J. Science Greaves M Maley CC. Clonal evolution in cancer J. Nature Loeb LA Loeb KR Anderson JP. Multiple mutations and cancer J. Proc Natl Acad Sci U S A Koebel CM Vermi W Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state J. Nature MacKie RM Reid R Junor B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery J. N Engl J Med Elder GJ Hersey P Branley P. Remission of transplanted melanoma clinical course and tumor cell characterisation J. Clin Transplant Suranyi MG Hogan PG Falk MC et al. Advanced donor-origin melanoma in a renal transplant recipient Immunotherapy cure and retransplantation J. Transplantation Rabinovich GA Gabrilovich D Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells J. Annual Rev Immunol Sakaguchi S Sakaguchi N Asano M et al. Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alpha-chains CD25. Breakdown of a single mechanism of selftolerance causes various autoimmune diseases J. J Immunol Deng L Zhang H Luan Y et al. Accumulation of foxp3 + T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients J. Clin Cancer Res Ostrand-Rosenberg S Sinha P. Myeloid-derived suppressor cells Linking inflammation and cancer J. J Immunol Thompson RH Gillett MD Cheville JC et al. Costimulatory B7- H1 in renal cell carcinoma patients Indicator of tumor aggressiveness and potential therapeutic target J. Proc Natl Acad Sci U S A Denardo DG Brennan DJ Rexhepaj E et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy J. Cancer Discov Vakkila J Lotze MT. Inflammation and necrosis promote tumor growth J. Nat Rev Immunol Blachere NE Darnell RB Albert ML. Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation J. PLoS Biol e Casares N Pequignot MO Tesniere A et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death J. J Exp Med Obeid M Tesniere A Ghiringhelli F et al. Calreticulin exposure dictates the immunogenicity of cancer cell death J. Nat Med Apetoh L Ghiringhelli F Tesniere A et al. Toll-like receptor 4- dependent contribution of the immune system to anticancer chemotherapy and radiotherapy J. Nat Med Ghiringhelli F Apetoh L Tesniere A et al. Activation of the NL- RP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors J. Nat Med Shiratsuchi A Watanabe I Takeuchi O et al. Inhibitory effect of Toll-like receptor 4 on fusion between phagosomes and endosomes / lysosomes in macrophages J. J Immunol Zitvogel L Apetoh L Ghiringhelli F et al. The anticancer immune response Indispensable for therapeutic success J. J Clin Invest Dougan M Dranoff G. Immune therapy for cancer J. Annu Rev Immunol Hudis CA. Trastuzumab mechanism of action and use in clinical practice J. N Engl J Med Spector NL Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2- positive breast cancer J. J Clin Oncol Park S Jiang Z Mortenson ED et al. The therapeutic effect of anti-her2 / neu antibody depends on both innate and adaptive immunity J. Cancer Cell Abes R Gelize E Fridman WH et al. Long-lasting antitumor protection by anti-cd20 antibody through cellular immune response J. Blood Smyth MJ Stagg J. Her 2 in 1 J. Cancer Cell Yang Y Li X Wang Y et al. CD8 + T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model J. Chinese Science Bulletin Kim MY Oskarsson T Acharyya S et al. Tumor self-seeding by circulating cancer cells J. Cell Casares N Arribillaga L Sarobe P et al. CD4 + /CD25 + regulatory cells inhibit activation of tumor-primed CD4 + T cells with IFN-gamma-dependent antiangiogenic activity as well as longlasting tumor immunity elicited by peptide vaccination J. J Immunol Morse MA Hobeika AC Osada T et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines J. Blood Kudo-Saito C Schlom J Camphausen K et al. The requirement of multimodal therapy vaccine local tumor radiation and reduc-

10 tion of suppressor cells to eliminate established tumors J. Clin Cancer Res Hodi FS O'Day SJ McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma J. N Engl J Med Robert C Thomas L Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma J. N Engl J Med Wang S Chen L. Immunobiology of cancer therapies targeting CD137 and B7-H1 /PD-1 cosignal pathways J. Curr Top Microbiol Immunol Brahmer JR Drake CG Wollner I et al. Phase Ⅰ study of single-agent anti-programmed death-1 MDX-1106 in refractory solid tumors Safety clinical activity pharmacodynamics and immunologic correlates J. J Clin Oncol Dudley ME Wunderlich JR Robbins PF et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes J. Science Gattinoni L Powell DJ Jr Rosenberg SA et al. Adoptive immunotherapy for cancer Building on success J. Nat Rev Immunol 檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿 Indoleamine 2 3-dioxygenase 1 IDO1 dendritic cell DC IDO1 CD11cloB220hi plasmacytoid DC pdc DC Ⅰ IFN-α IFN-β T IFN-γ pdc IDO1 T β transforming growth factor β TGF-β pdc IDO1 IDO1 TGF-β CD8 - DC pdc naive T TGF-β pdc T Treg sirna IDO1 TGF-β IDO1 1-MT IDO1 TGF-β TGF-β pdc TGF-β IDO1 pdc TGF-β IL-6 IL-27 T Treg CD4 + T TGF-β pdc IDO1 Treg IDO1 TGF-β IDO1 IDO1 immunoreceptor tyrosine-based inhibitory motif ITIM ITIM SHP-1 SHP-2 TGF-β pdc PI3K Fyn IDO1 IDO1 ITIM SHP-1 SHP-2 IDO1 SHP-1 SHP-2 NF-κB p52 RelB IDO1 Ⅰ TGF-β Ⅰ TGF-β naive T Treg TGF-β pdc IDO1 TGF-β pdc Treg 3 IDO1 IDO1 TGF-β. Pallotta MT Orabona C Volpi C et al. Nat Immunol