靶向跨膜肿瘤坏死因子 α 的 CAR-T 细胞联合 PD-1 单抗对乳腺癌的抗肿瘤作用

Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF- ) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.

We generated CAR-T cells targeting tmTNF- but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF- -expressing breast cancer cells in vitro and in vivo.

Our tmTNF- CAR-T cells showed potent cytotoxicity against tmTNF- -expressing breast cancer cells but not tmTNF- -negative tumor cells with increased secretion of interferon gamma (IFN- ) and interleukin (IL)-2 in vitro. In tmTNF- -overexpressing TNBC-bearing mice, the tmTNF- CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN- and IL-2. However, we found thattmTNF- induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF- B and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF- CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy.

Our findings suggest a potent antitumor efficacy of the tmTNF- CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF- signaling, indicating a promising individual therapy for tmTNF- -positive breast cancers including TNBC.