Chemotherapeutic targeting of cancer-induced immunosuppressive cells

Abstract

The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumors to escape from detection and elimination by the immune system. Regulatory T lymphocytes (Treg) and myeloid-derived suppressor cells (MDSC), major components of these inhibitory cellular networks, have drawn intense scrutiny in recent years. In patients with cancer and in animal tumor models, these suppressor cells accumulate in the tumor microenvironment, secondary lymphoid tissues, and in the blood. Equipped with the ability to suppress innate and adaptive anticancer immunity, these cells also foster disease development by promoting tumor neoangiogenesis and by enhancing cancer metastasis. They therefore represent major impediments for anticancer therapies, particularly for immune-based interventions. Recent work has provided evidence that beyond their direct cytotoxic or cytostatic effects on cancer cells, several conventional chemotherapeutic drugs and agents used in targeted therapies can promote the elimination or inactivation of suppressive Tregs or MDSCs, resulting in enhanced antitumor immunity. We analyze findings pertinent to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents, and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer chemoimmunotherapeutic strategies.

Figure 1. Elimination, inactivation or reprograming of tumor-induced Treg and MDSC by conventional chemotherapeutic drugs or targeted therapeutic agents

Treg and MDSC critically contribute to the immunosuppressive environment associated with developing cancers. These cells blunt antitumor immunity by suppressing effector CD4⁺ Th, CD8⁺ CTL, NK, macrophages or dendritic cells. A selective list of conventional chemotherapeutic drugs or targeted therapeutic molecules are endowed with the ability to promote antitumor immunity and foster the efficacy of immunotherapeutic interventions by enhancing the function of immune effector cells or by reversing immunosuppression induced by Treg and MDSC. Antineoplastic agents can selectively trigger death of suppressive cells, inhibit their function or foster their differentiation into proinflammatory subsets devoid of inhibitory properties. Ag, Tumor-derived antigens; CTL, Cytotoxic T Lymphocytes; DC, Dendritic Cells; ICD, Immunogenic Cell Death; Th, T helper lymphocytes.