| Author |
Pei, SY; Deng, XY; Yang, RR; Wang, H; Shi, JH; Wang, XQ; Huang, J; Tian, Y; Wang, RJ; Zhang, SL; Hou, H; Xu, J; Zhu, QC; Huang, H; Ye, JL; Wang, CY; Lu, W; Luo, QQ; Ni, ZY; Zheng, MY; Xiao, YC |
| Abstract |
Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8(+) tissue resident memory T (T-RM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8(+) T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8(+) T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated T-RM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8(+) T cells by restoring T-RM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8(+) T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced T-RM restriction as a key mechanism causing aged CD8(+) T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy. |
