Validation of novel peptides potentially inhibitory of the MIF/CD74 axis as a strategy for reversing the tumor microenvironment immunotolerance: a preclinical approach for the treatment to metastatic melanoma

Abstract

Cutaneous melanoma is a letal type of skin cancer in which the therapeutic resistance is associated to a modulated tumor microenvironment. Although of melanoma cells are uniquely immunogenic, they adapt to suppress innate and adaptive immunity by expressing several factors that play a central role in immunoediting. One of these cytokines is the macrophage migration inhibitory factor (MIF), which plays an important tolerogenic role favoring the tumor growth. It is highly expressed by the melanoma cells and stromal cells to modulate the immunosuppressive cytokine profile in the tumor microenvironment. The binding of MIF to its main receptor, the CD74, forms the active complex with CD44, which initiates a signaling that involves activation of NF-ºB and Erk1/2 and induction of secretion of pro-inflammatory cytokines. This signaling exerts effects on TAMs, DCs, regulatory T lymphocytes and MDSCS, promoting tumor immunoediting that results in the functional blockade of the innate and adaptive response. Preliminary results generated by our collaborator at the University of Liverpool/UK showed that the secretion products of B16F10 melanoma cells in the metastatic site, with the predominant participation of MIF, favor a tolerogenic response by DCs and macrophages. The presence of CD74, in these studies, was confirmed in a immortalized macrophage model, as well as in primary cultures of bmDCs and bmMOs. Understanding the role of MIF/CD74 axis in the context of immunoediting of the tumor microenvironment, correlation with acquired resistance and possible application of new potentially inhibitory peptides acting on this axis, associated with clinically approved treatments, constitute the object of study of this project. It aims at increasing the effectiveness of therapeutic protocols in use. The preclinical proposition of a new immune-associated approach for the treatment of metastatic melanoma would be the basis for a new protocol. In summary, the functional blockade of the MIF/CD74 axis with our peptides C36, RIC1, and RIC2, in combination with currently approved immunotherapies and target therapies (e.g., anti-PD-1 and sorafenib), seek an increased efficacy and reduced resistance in melanoma treatment.