Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has achieved successful outcomes against hematological malignancies and provided a new impetus for treating solid tumors. However, the efficacy of CAR-T cells for solid tumors remains unsatisfactory. The tumor microenvironment has an important role in interfering with and inhibiting the effector function of immune cells, among which upregulated inhibitory checkpoint receptors, soluble suppressive cytokines, altered chemokine expression profiles, aberrant vasculature, complicated stromal composition, hypoxia and abnormal tumor metabolism are major immunosuppressive mechanisms. In this review, we summarize the inhibitory factors that affect the function of CAR-T cells in tumor microenvironment and discuss approaches to improve CAR-T cell efficacy for solid tumor treatment by targeting those barriers.

Keywords: CAR-T; Microenvironment; Tumor.

Fig. 1

Schematic diagram of the solid tumor microenvironment. The solid tumor microenvironment consists of the extracellular matrix, abnormal tumor vasculature, various cells, soluble molecules, and physiological and biochemical components produced by special tumor metabolism. The extracellular matrix together with the abnormal tumor vasculature form a physical barrier to T cell entry. Cells include tumor cells, effector immune cells, inhibitory immune cells, and stromal cells, such as cancer-associated fibroblasts (CAFs). Tumor cells usually express some inhibitory ligands or receptors, such as PD-L1/L2, to interfere with the function of T cells; other inhibitory immune cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory cells (Tregs), further inhibit the function of effector T cells. Soluble molecules such as chemokines, cytokines, and other factors act to regulate tumor vessels, such as vascular endothelial cell growth factor (VEGF) and andothelin-1. VEGF and andothelin-1 interact with VEGFR and endothelin B receptor (ET_BR) on tumor vessels, respectively, to promote angiogenesis or downregulate the expression of adhesion molecules. While some chemokines contribute to recruiting effector immune cells, others recruit inhibitory immune cells such as MDSCs and Tregs. Cytokines include effector cytokines (not indicated) and inhibitory cytokines such as IL-4 and TGF-β. Anomalous tumor metabolism produces a series of metabolites and induces hypoxia, which severely affects the survival and proliferation of T cells

Fig. 2

Strategies to overcome barriers of CAR-T cells in the solid tumor microenvironment. a Combining CAR-T cells with PD-1, PD-L1, and CTLA-4 blockades, transducing genes of anti-PD-1/PD-L1/CTLA-4 antibodies/secreting scFvs into CAR-T cells, or knocking out checkpoint genes in CAR-T cells to block the inhibitory signal of CAR-T cells. b Expressing chemokine receptors in CAR-T cells to improve their tumor-directed trafficking or blocking chemokines and receptors expressed by tumor cells or stromal cells to inhibit the recruitment of inhibitory immune cells. c Disrupting the tumor vasculature with anti-VEGFR CAR or inhibiting tumor angiogenesis by blocking VEGF or promoting the infiltration of CAR-T cells by blocking ET_BR to inhibit its function on downregulation of adhesion molecules, inhibiting RGS5 signaling to normalize pericytes and tumor vasculature, and upregulating expression of adhesion molecules on a blood vessel by NGR-TNF and RGR-TNF. d Simultaneously targeting stromal cells and tumor cells by FAP and tumor antigen dual-targeting CAR or engineering CAR-T cells to secrete heparanase to degrade tumor extracellular matrix. e Inhibiting IDO, PKA, and ROS by inhibitors or RIAD-CAR-T cells (RIAD is a blocking peptide that inhibits the function of PKA) to eliminate their negative effects on CAR-T cells or engineering CAR-T cells to express enzymes such as catalase that clear ROS. f Depleting immune-inhibitory cells such as MDSCs and Tregs by antibodies or inhibitors and blocking inhibitory cytokines such as IL-4 and TGF-β with CAR-T cells expressing modified receptors. PD-1 Programmed death-1, PD-L1 Programmed death-ligand 1, CTLA-4 Cytotoxic T-lymphocyte-associate protein-4, VEGF Vascular endothelial cell growth factor, VEGFR Vascular endothelial cell growth factor receptor, ET_BR Endothelin B receptor, RGS5 regulator of G-protein signaling 5, NGR-TNF/RGR-TNF Vascular-targeting agents, coupling the angiogenic vessel-homing peptide with tumor necrosis factor-α, FAP Fibroblast activation protein, IDO Indoleamine 2,3 dioxygenase, PKA Protein kinase A, ROS Reactive oxygen species, RIAD Regulatory subunit I anchoring disruptor, a PKA-inhibiting peptide, DNRII Dominant-negative mutation of the TGF-β type II receptor, ATRA all-trans retinoic acid, PDE5 Phosphodiesterase-5, VD3 Vitamin D3