Tumor-Initiated Inflammation Overrides Protective Adaptive Immunity in an Induced Melanoma Model in Mice

Abstract

We studied the effect of the immune system on two differentially aggressive melanomas developing in mice on conditional deletion of the INK4A/ARF tumor suppressor gene, with concomitant expression of oncogene H-Ras G12V and a natural cancer-germline tumor antigen (TA). "Slow progressor" melanomas contained no activated T lymphocytes (TL). In contrast, "aggressive" melanomas were infiltrated by activated TLs lacking effector molecules and expressing high levels of PD-1, indicating an exhausted phenotype. Aggressive melanomas were also infiltrated by immature myeloid cells (IMC). Infiltration was associated with local inflammation and systemic Th2/Th17-oriented chronic inflammation that seemed to impair further activation of TLs, as tumor-specific T cells adoptively transferred into mice bearing aggressive melanomas were poorly activated and failed to infiltrate the melanoma. This immunosuppression also led to the incapacity of these mice to reject inoculated TA-positive tumors, in contrast to slow-progressing melanoma-bearing mice, which were responsive. To test the role of adaptive immunity in tumor progression, we induced melanomas in immunodeficient RagKO compound mice. These mice developed aggressive but not slow-progressing melanomas at a higher frequency and with a shorter latency than immunocompetent mice. Immunodeficient mice also developed abnormal inflammation and infiltration of IMCs in a manner similar to immunocompetent mice, indicating that this phenotype was not dependent on adaptive immunity. Therefore, tumor-intrinsic factors distinguishing the two melanoma types control the initiation of inflammation, which was independent of adaptive immunity. The latter delayed development of aggressive melanomas but was overridden by inflammation. Cancer Res; 70(9); 3515-25. ©2010 AACR.

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

“…In the aggressive melanoma developed in mice on conditional deletion of the INK4A/ARF tumor suppressor genes with concomitant expression of H-RasG12V, Tregs significantly accumulate in TdLNs and tumors (25). In MT/ret mice, we found that Treg infiltration remained marginal in cutaneous metastases.…”

Active STAT5 Regulates T-bet and Eomesodermin Expression in CD8 T Cells and Imprints a T-bet–Dependent Tc1 Program with Repressed IL-6/TGF-β1 Signaling

“…In a mouse model (TiRP) of autochthonous melanomas (51), aggressive melanoma development was associated with increased levels of several immune-modulating cytokines in the sera (52), including IL-6, a well-known inducer of STAT3 (19). Indeed, p-STAT3 was detected in tumor cells and in some hematopoietic cells infiltrating the TiRP melanoma tumors (52). Additionally, those TiRP tumors were infiltrated by T cells with low levels of GzmB effector molecules and presenting an "exhausted" programmed death-1 + phenotype (52).…”

“…Indeed, p-STAT3 was detected in tumor cells and in some hematopoietic cells infiltrating the TiRP melanoma tumors (52). Additionally, those TiRP tumors were infiltrated by T cells with low levels of GzmB effector molecules and presenting an "exhausted" programmed death-1 + phenotype (52). We recently showed (20) that adoptive transfer of tumor-specific eTCs-STAT5CA was efficient at inducing melanoma regression.…”

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

“…Whether this mostly results from the increased frequency of anti-P1A [35][36][37][38][39][40][41][42][43] CD8 T lymphocytes or from a wider P1A [35][36][37][38][39][40][41][42][43] -specific TCR repertoire, or both, will require further studies (42). The relevance of such studies will be further increased by their association with a model of spontaneous tumors expressing the P1A-encoded tumor Ag (43,44).…”