http / /www. biother. org Chin J Cancer Biother Jun. 2012 Vol. 19 No. 3 DOI 10. 3872 /j. issn. 1007-385X. 2012. 03. 001 229 100101 1988 1998 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 E-mail sdwang@ moon. ibp. ac. cn R730. 2 R730. 3 R730. 5 A 1007-385X 2012 03-0229-10 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 100101 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. 2012CB917100 No. 91029719 Project supported by the Grant from the National Basic Research Development Program of China 973 Program No. 2012CB917100 and the Major Research Plan of the National Natural Science Foundation of China No. 91029719 http / /www. cnki. net /kcms /detail /31. 1725. R. 20120529. 1705. 008. html
230 2012 6 19 3 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 2012 19 3 229-238 dormant 1 1. 1 1909 Paul Ehrlich 50 Sir. Macfarlane Burnet Lewis Thomas tumor immunosur- veillance myeloid derived suppressor cell MDSC 2-3 20 90 1 3 1. 2
. 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 4 1 9 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 20 10 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
232 2012 6 19 3 50% 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 12 2 16 1 13-14 Treg Treg 15 17 MDSC 1% 4 ~ 10 1. 4 MDSC NK NKT CD4 + CD8 + T 18 TAM M2 15 1 MHC I TAP1 LMP2 LMP 7 CTL NKG2D NK Treg 15 17 2 B7-H1 19 B7-H1 PD-L1T T T 20 Fas 2 FasL 100 3 TGF-β IL-10 IDO VEGF T
. 233 22-23 23-24 CD4 + CD8 + T DC CD11c-DTR 23-25 T IFN-γ IL-1β IFN-γ IL-1β IFN-γ IL-1β DC T CTL Obeid 24 2. 1 necrosis CRT IL-8 IL-10 TNF-α CRT DC HMGB1 DC apoptosis CRT sirna CRT DC C1q CRT phosphatidylserine PS calreticulin CRT CD47 24-26 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
234 2012 6 19 3 27 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 30-31 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
. 235 3 T CD20 T 33 HER2 /neu T 4-1BB CD137 CD40 PD-1 IL- 15R /IL-15 HER2 / neu 32 34 CD8 + T CD8 + T CD8 + T 4-1BB 35 T 36 CD25 Treg 37
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