Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CART cells, its effect on human CART cells has not been fully elucidated. In particular, there was no evaluation of the CART cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CART cells, and only A2AR was responsible for adenosine-induced impairment of CART cell function. Disrupting A2AR gene in human CART cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CART cells in vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy of A2AR knockout CART cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate that A2AR knockout CART cells have the potential of being an improved CART cell therapy in treating solid tumors.

Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners

“…Targeting the CD73/adenosine pathway is another interesting approach for combination therapy with CAR T cells ( Table 2 ). Adenosine represents a very important immunosuppressive metabolite in the tumor microenvironment of solid tumors [ 149 ]. While both adenosine A 2A and A 2B receptors are upregulated in human CAR T cells, adenosine-mediated suppression of CAR T cell effector function was mediated by the adenosine A 2A receptor [ 149 ].…”

“…Adenosine represents a very important immunosuppressive metabolite in the tumor microenvironment of solid tumors [ 149 ]. While both adenosine A 2A and A 2B receptors are upregulated in human CAR T cells, adenosine-mediated suppression of CAR T cell effector function was mediated by the adenosine A 2A receptor [ 149 ]. Activation of CAR T cells led to enhanced adenosine A 2A receptor expression and therefore resulted in CAR T cell suppression [ 119 ].…”

How Can We Engineer CAR T Cells to Overcome Resistance?

“…• Receptor inhibition/knockout eg Adenosine receptor [172][173][174][175] • Manipulation of inhibitory pathways in CAR T cells 176 Low availability of nutrients in TME Malignant cells accelerate metabolism reducing the availability of nutrients for CAR T cells and increasing harmful by products…”

“…172 Alternatively, CAR T cells deficient in the adenosine receptor A 2A showed improved in vivo anti-tumour responses associated with increased cytokine production. [173][174][175] Prostaglandin E 2 (PGE 2 ) is also produced within the TME by tumour-derived cyclooxygenase 2 (COX2)mediated conversion of arachidonic acid. Similar to adenosine, PGE 2 binds receptors that are found on T cells, resulting in PKA activation.…”

Impact of genomic preselection on subsequent genetic evaluations with ssGBLUP - using real data from pigs

“…However, despite much effort, solid tumors have proved largely unresponsive due to inefficient infiltration of CAR T cells, presence of immunosuppressive tumor microenvironment and exhaustion of T cells 1,6,7 . Various strategies have been attempted to potentiate CAR-T cells targeting solid tumors, including the expression of chemokine receptors [8][9][10] , disruption of the inhibitory adenosine and TGF-β signaling via deletion of adenosine and TGF-β receptor A2AR and TGFBR2, respectively 11,12 , administration of IL-7, IL-15 or IL-21 [13][14][15] , use of immune checkpoint inhibitors [16][17][18] , or deletion of PD-1 gene in CAR T cells [19][20][21] , but their benefits are limited. For example, the use of immune checkpoint inhibitors in conjunction with CAR T therapy may increase the risk of autoimmunity, while PD-1 knockout may lead to the failure of CD8+ T cells, as PD-1 expression can protect CD8+ T cells from excessive proliferation and terminal differentiation 22 .…”