Immunsuppressive Pathways in Melanoma

Melanoma is known for its poor response to current immunotherapies. Insufficient anti-tumor reactivity could be due to the formation of a chronic inflammation, leading to a profound immunosuppression. Using the ret transgenic murine melanoma model that mimics human melanoma, we found in skin tumors and metastatic lymph nodes increased levels of chronic inflammatory factors (IL-1beta, IL-6, IFN-gamma, TNF-alpha etc.) associated with the accumulation of myeloid-derived suppressor cells (MDSC) known to inhibit tumor infiltrating T cells. The accumulation of CD11b+Gr1+ MDSC in melanoma lesions was associated with upregulation of CCR5 expression on these cells. Concentration of CCR5 ligands chemokines CCL3, CCL4 and CCL5 was significantly elevated in melanoma lesions as compared to serum of tumor-bearing mice. CCR5-positive MDSC displayed a significantly higher immunosuppressive activity than their CCR5-negative counterparts. MDSC were also shown to express ectonucleotidases CD39 and CD73 stimulating the production of adenosine that strongly inhibits T cell functions. Tumor-infiltrating T cells expressed not only markers of activated or memory cells but also CD39 and CD73 that were up-regulated by tumor-derived soluble factors (like TGF-beta). This suggests that adenosine producing by effector T cells can inhibit their anti-tumor reactivity via autocrine signaling as a part of the negative feedback loop.

In melanoma patients, we found that the level of serum IL-1beta, IFN-gamma, CXCL10 and the frequency of circulating monocytic MDSC were strongly increased in advanced melanoma patients that significantly correlated with a decreased progression free survival of these patients. Our data suggest that chronic inflammatory mediators, MDSC and adenosine metabolism in melanoma patients are of importance for the pathogenesis and prognosis of melanoma progression and could help to identify patients with high risk of disease progression.