Targeting the DNA damage response enhances CD70 CAR-T cell therapy for renal carcinoma by activating the cGAS-STING pathway

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has shown tremendous success in eradicating hematologic malignancies. However, this success has not yet been extrapolated to solid tumors due to the limited infiltration and persistence of CAR-T cells in the tumor microenvironment (TME). In this study, we screened a novel anti-CD70 scFv and generated CD70 CAR-T cells that showed effective antitumor functions against CD70+ renal carcinoma cells (RCCs) both in vitro and in vivo. We further evaluated the effect and explored the molecular mechanism of a PARP inhibitor (PARPi) in CAR-T cell immunotherapy by administering the PARPi to mouse xenografts model derived from human RCC cells. Treatment with the PARPi promoted CAR-T cell infiltration by stimulating a chemokine milieu that promoted CAR-T cell recruitment and the modulation of immunosuppression in the TME. Moreover, our data demonstrate that PARPi modulates the TME by activating the cGAS-STING pathway, thereby altering the balance of immunostimulatory signaling and enabling low-dose CAR-T cell treatment to induce effective tumor regression. These data demonstrate the application of CD70 CAR-T cell therapeutic strategies for RCC and the cross-talk between targeting DNA damage responses and antitumor CAR-T cell therapy. These findings provide insight into the mechanisms of PARPis in CAR-T cell therapy for RCC and suggest a promising adjuvant therapeutic strategy for CAR-T cell therapy in solid tumors.

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…Apart from immune checkpoint blockade therapy, chimeric antigen receptor T cell (CAR-T) immunotherapy has not been applied to solid tumors. However, olaparib has been shown to enhance CAR-T in the treatment of renal cancer and breast cancer models [ 129 , 130 ].…”

“…For example, PARPi promotes CAR-T infiltration in the TME via the cGAS-STING pathway. Specifically, PARPi promotes the upregulation of both IFN-β expression and chemokines via the STING-TBK1-IRF3 pathway, leading to CD8+ CAR-T cell recruitment and the secretion of large amounts of granzyme B [ 129 ]. This process ultimately allows low-dose CAR-T cell treatment to induce effective tumor regression in mice with kidney cancer [ 129 ].…”

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

“…FEN1 was found to interact with various proteins to exert its activity in BER. PARP (Poly ADP-ribose polymerase), a key enzyme in the repair of DNA damage, is a superfamily of multi-domain proteins [ 30 ]. Each PARP protein has a highly conserved (ADP-ribosyltransferase) domain that can catalyze the transformation of nicotinamide lysed adenine dinucleotide (NAD+) into nicotinamide and ADP-ribose [ 31 ].…”

Co-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis

“…Previous studies show that the CD70-CD27 axis promotes T cell survival and cytotoxicity, and the production and amplification of virus-specific memory T cells 8,10 . Recent studies reports that anti-CD70 CAR T cells exhibit effective antitumor functions against renal carcinoma and acute myeloid leukemia (AML) 64,65 . In addition, CD27 co-stimulation augments the survival and antitumor activity of CAR T cells 66,67 .…”