MDSC: a new potential breakthrough in CAR-T therapy for solid tumors

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice.

Keywords: Chimeric antigen receptor T (CAR-T); Myeloid-derived suppressor cells (MDSCs); Solid tumor; Tumor microenvironment (TME).

Fig. 1

MDSCs promote tumor progression and metastasis via formation of TME. A MDSCs directly enhance tumor proliferation. B MDSCs promote tumor migration and invasion by regulating the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) of tumor cells. C MDSCs promote the extravasation of circulating tumor cells (CTCs). D MDSCs induce angiogenesis in order for CTCs to colonize the pre-metastasis niche (PMN) efficiently

Fig. 2

MDSCs play a tumor-promoting role by antagonizing T cell activity. The function of T cells in the TME is significantly impeded by MDSCs via (A) Exhaustion of L-arginine, cystine, and cysteine. B Production of ROS and RNS. C Production of immunosuppressive cytokines such as IL-10, TGFβ1, and IL-6 and induction of Tregs. D Expression of inhibitory receptors such as, PD-L1

Fig. 3

Target MDSCs in solid tumor for effective CAR-T immunotherapy. Therapeutic strategies include (A) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (B) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (C) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (D) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (E) CAR-T directly targeting MDSC selective antigens