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.
Highlights
The discovery of melanoma antigens recognized by autologous T lymphocytes (TL) has led to clinical protocols designed to mobilize tumor antigen (TA)–specific TL in patients with melanoma by vaccination or by adoptive transfer of TA-specific TL
We show that tumor-intrinsic factors differentiate these melanoma types and control the initiation of inflammation, which was independent of adaptive immunity
Inflammation as a result of an oncogenic process or of adaptive immunity? Innate and adaptive immunity have both been implicated in resistance to spontaneous and carcinogen-induced tumors in mice [13]
Summary
The discovery of melanoma antigens recognized by autologous T lymphocytes (TL) has led to clinical protocols designed to mobilize tumor antigen (TA)–specific TL in patients with melanoma by vaccination or by adoptive transfer of TA-specific TL. The efficacy of these treatments remains poor [1,2,3]. Authors' Affiliations: 1Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée; 2Institut National de la Sante et de la Recherche Medicale, U631; 3Centre National de la Recherche Scientifique, UMR6102, Marseille, France and 4Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université Catholique de Louvain, Brussels, Belgium. Huijbers: The Institute of Cancer Research, London SW3 6JB, United Kingdom
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