Abstract
Immune checkpoint inhibitors (ICI) used for cancer immunotherapy were shown to boost the existing anti-tumor immune response by preventing the inhibition of T cells by tumor cells. Antibodies targeting two negative immune checkpoint pathways, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1), have been approved first for patients with melanoma, squamous non-small cell lung cancer (NSCLC), and renal cell carcinoma. Clinical trials are ongoing to verify the efficiency of these antibodies for other cancer types and to evaluate strategies to block other checkpoint molecules. However, a number of patients do not respond to this treatment possibly due to profound immunosuppression, which is mediated partly by myeloid-derived suppressor cells (MDSC). This heterogeneous population of immature myeloid cells can strongly inhibit anti-tumor activities of T and NK cells and stimulate regulatory T cells (Treg), leading to tumor progression. Moreover, MDSC can contribute to patient resistance to immune checkpoint inhibition. Accumulating evidence demonstrates that the frequency and immunosuppressive function of MDSC in cancer patients can be used as a predictive marker for therapy response. This review focuses on the role of MDSC in immune checkpoint inhibition and provides an analysis of combination strategies for MDSC targeting together with ICI to improve their therapeutic efficiency in cancer patients.
Highlights
Cancer immunotherapy has become a promising approach to treat patients over the past decade [1]
Activated myeloid-derived suppressor cells (MDSC) produce elevated levels of nitric oxide (NO) via inducible nitric oxide synthase and upregulate the expression of arginase-1 (ARG-1), both leading to cell cycle arrest in T cells via depletion of the amino acid l-arginine from the tumor microenvironment [41, 42] and to T cell anergy induced by the downregulation of T cell receptor (TCR) ζ-chain expression [16, 43]
Immune checkpoint inhibitors for cancer therapy are approved for the treatment of cutaneous melanoma, non-small cell lung cancer (NSCLC), kidney cancer, bladder cancer, head and neck cancers, Merkel cell carcinoma, gastric cancer, and Hodgkin lymphoma and could significantly improve the clinical outcome of cancer patients
Summary
Cancer immunotherapy has become a promising approach to treat patients over the past decade [1]. Signals transmitted to T cells either via programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) promote T cell anergy and thereby switch off the immune response Blockers of these immune checkpoint molecules have been shown to restore an immune response against cancer and increase patient survival [4, 5]. Despite the fact that these immune checkpoint inhibitors (ICI) have proved to be effective, therapeutic resistance occurs in the majority of patients, leading to tumor progression [5, 6]. This occurs due to the immunosuppressive tumor microenvironment represented by several immunosuppressive factors and cells, including myeloid-derived suppressor cells (MDSC) [7,8,9,10].
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