Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice.
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.
Soudja
Saïdi M
SM
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Institut National de la Sante et de la Recherche Medicale, U631 Centre National de la Recherche Scientifique, UMR6102, Marseille, France.
Wehbe
Maria
M
Mas
Amandine
A
Chasson
Lionel
L
de Tenbossche
Céline Powis
CP
Huijbers
Ivo
I
Van den Eynde
Benoît
B
Schmitt-Verhulst
Anne-Marie
AM
D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D016219:Immunotherapy, Adoptive; D007249:Inflammation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018631:ras Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics
D000951:Antigens, Neoplasm; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018984:Epitopes, T-Lymphocyte; C507749:cancer-testis antigen P1A, mouse; D018631:ras Proteins