Immune checkpoint inhibitors increased overall survival for patients with advanced and metastatic melanoma, but long-term treatment responses are still limited to few patients with tumor specific effector T-cells at the tumor sites as predictors for treatment success. Thus, new treatment strategies are required. In preclinical models we could recently show, that targeted activation of melanoma-associated mast cells (MC) with lipopolysaccharide (LPS) induces an effective anti-melanoma immune response in a Toll-like receptor (TLR) 4-dependent manner. Tumor control was mediated by MC-derived CXCL10, a T cell recruiting chemokine whose expression positively correlates with survival of melanoma patients. Like LPS, Hsp70 can also activate the TLR4 pathway and extracellular Hsp70 was shown to stimulate immune responses in a variety of cancers. We therefore investigated the impact of Hsp70 on melanoma and its environmental immune cells. In in vitro studies we could demonstrate that Hsp70 activates mast cells in a TLR4-dependent manner and leads to secretion of CXCL10. Repeated peritumoral application of Hsp70 in a B16 mouse melanoma model resulted in tumor control with enhanced tumor-infiltrating lymphocytes and in increase of TNF-a and IFNy producing T cells in the draining lymph nodes. The combination of the Hsp70 treatment with anti-CTLA-4 immunotherapy further augmented anti-melanoma efficacy. Collectively, combined Hsp70 administration with immune checkpoint therapy represents a highly efficient anti-tumor modality, and is promising for clinical translation.

ESDR196 - Effective anti-melanoma immune response by peritumoral delivery of the heat shock protein 70 (Hsp70)

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING