Speaker: Dr. Paula Granado Martínez, Biomedical Research in Melanoma (VHIR)

Immune-based therapies have dramatically changed the management of many types of cancers including melanoma. However, the lack of clear biomarkers for the response or resistance to immunotherapy makes it only effective in a limited fraction of patients. Therefore, there is an unmet need to better understand the molecular mechanisms governing tumor evasion to develop and administer the most effective cancer treatment. In this matter, not much is known on how oncogenic pathways influence the immune infiltrate and this might have a significant impact on therapies.
Although RAS pathway activation is a central event in melanoma, the MAPK stress pathway plays an important role in several processes related to the melanoma development and progression, including the signaling of several cytokines that modulate and activate the immune system. Our data shows that spontaneous mouse tumors and human samples harbor genetic alterations in this pathway, including the upregulation of p38á. Importantly, p38á upregulation is associated to poor survival in an independent manner, and reduces the survival of patients harboring BRAFV600E and NRASQ61 mutations. Moreover, p38á regulates the expression of immuno-checkpoint molecules in tumor cells and limits the antitumoral cytotoxic response modifying specific immune cell populations of tumor inflammatory infiltrates, possibly determining the response to immunotherapy. Therefore, our results suggest that inhibition of p38á or its downstream effectors in combination with immune-based therapies could be used as a new therapeutic approach for the treatment of melanoma.

Host: Dr. Juan Ángel Recio, Biomedical Research in Melanoma (VHIR)