Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target

Abstract

Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.

Figure 1. MDSC accumulation, recruitment, and functions in the TME.

Inflammatory mediators released by host cells lead to the dysregulation of normal myelopoiesis and to the accumulation of MDSCs in the bone marrow. MDSCs expand and migrate to the TME through the interaction between CCR and CXCR and their corresponding chemokine ligands. In the TME, MDSCs are activated, and promote immunosuppression and tumor growth via various mechanisms. These mechanisms involve inhibiting the functions of T cells, NK cells, and DCs, promoting the differentiation of M2 macrophages, Tregs, and Bregs, and inducing angiogenesis and metastasis. Breg, regulatory B cell; CMP, common myeloid progenitor; HSC, hematopoietic stem cell.

Figure 2. Potential therapeutic approaches to target MDSCs.

The main strategies to target MDSCs include MDSC depletion (A); inhibition of MDSC suppressive functions (B); blocking of MDSC expansion and recruitment (C); promotion of MDSC differentiation (D); and inhibition of MDSC metabolism (E). Relevant MDSC mechanisms are illustrated in each panel, and examples for each type of therapeutic approach are listed. AA, arachidonic acid; CMP, common myeloid progenitor; CPT1, carnitine palmitoyltransferase 1; FAO, fatty acid oxidation; FFAs, free fatty acids; GO, gemtuzumab ozogamicin; HSC, hematopoietic stem cell; TKIs, tyrosine kinase inhibitors; TSA, trichostatin A.