黄芪多糖通过增加 CD122(+)CXCR3(+)PD-1(-) 记忆 T 细胞增强嵌合抗原受体工程化 (CAR) T 细胞的抗肿瘤作用

Chimeric antigen receptor-engineered T (CAR-T) cell therapy of cancer has been a hotspot and promising.

However, due to rapid exhaustion, CAR-T cells are less effective in solid tumors than in hematological ones. CD122 + CXCR3 + memory T cells are characterized with longevity, self-renewal and great antitumoral capacity.

Thus, it's compelling to induce memory CAR-T cells to enhance their efficacy on solid tumors. Astragalus polysaccharide (APS) has reportedly exhibited antitumoral effects.

However, it's unclear if APS has an impact on CD8 + memory T cell generation or persistence. Using two human cancer cell lines, here we found that APS significantly improved the persistence of GPC3-targeted CAR-T cells and enhanced their suppression of tumor growth in both Huh7 and HepG2 xenograft models of hepatocellular carcinoma. APS increased CD122 + /CXCR3 + memory T cells, but decreased their PD-1 + subset within CD8 + CAR-T cells in tumor-bearing mice, while these effects of APS were also confirmed with in vitro experiments.

Moreover, APS augmented the expression of chemokines CXCL9/CXCL10 by the tumor in vivo and in vitro. It also enhanced the proliferation and chemotaxis/migration of CAR-T cells in vitro.

Finally, APS promoted the phosphorylation of STAT5 in CD8 + CAR-T cells, whereas inhibition of STAT5 activation reversed these in vitro effects of APS.

Therefore, APS enhanced the antitumoral effects of CD8 + CAR-T cells by promoting formation/persistence of CD122 + /CXCR3 + /PD-1 - memory T cells and their migration to the tumor.