Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation |
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Authors: | Email author" target="_blank">Viktor?UmanskyEmail author Alexandra?Sevko |
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Institution: | (1) Skin Cancer Unit (G300), German Cancer Research Center and University Hospital Mannheim, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany |
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Abstract: | Malignant melanoma is known by its rapid progression and poor response to currently applied treatments. Despite the well-documented
melanoma immunogenicity, the results of immunotherapeutic clinical trials are not satisfactory. This poor antitumor reactivity
is due to the development of chronic inflammation in the tumor microenvironment characterized by infiltrating leukocytes and
soluble mediators, which lead to an immunosuppression associated with cancer progression. Using the ret transgenic mouse melanoma model that closely resembles human melanoma, we demonstrated increased levels of chronic inflammatory
factors in skin tumors and metastatic lymph nodes, which correlated with tumor progression. Furthermore, Gr1+CD11b+ myeloid-derived suppressor cells (MDSC), known to block tumor-reactive T cells, were enriched in melanoma lesions and showed
an enhanced immunosuppressive capacity. This MDSC accumulation was associated with a strong TCR ζ-chain downregulation in
T cells suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity.
Indeed, upon administration of phosphodiesterase-5 inhibitor sildenafil or paclitaxel in non-cytotoxic doses, we observed
reduced levels of chronic inflammatory mediators in association with decreased MDSC amounts and immunosuppressive function.
This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing
mice. CD8 T-cell depletion resulted in an abrogation of beneficial outcome of both drugs, suggesting the involvement of MDSC
and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment
should be applied in conjunction with melanoma immunotherapies to increase their efficacy. |
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