Title : Activin-A protects against lung cancer progression by boosting anti-tumor T cell responses
Activin-A is a pleiotropic cytokine that exerts diverse effects on immune responses depending on the spatiotemporal context; still its precise role in shaping anti-tumor T cell-mediated immune responses remains ill defined.
In order to evaluate whether activin-A directs effective, T cell-mediated anti-tumor responses during lung cancer development, we utilized a syngeneic mouse lung cancer model induced by Lewis Lung Carcinoma cells and administered activin-A therapeutically. In a complementary approach, we disrupted activin-A’s signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A’s type I receptor, ALK4. Using adoptive T cell transfer experiments, we evaluated whether ex vivo administration of activin-A on CD4+ T cell obtained from murine lung tumors, protects against lung tumor formation in CD4 KO recipients. Finally, in a preclinical setting, we examine the effects of ex vivo activin-A treatment on the phenotypic characteristics and effector capacity of tumor-infiltrating T cells from lung cancer patients.
Our findings reveal that activin-A administration led to a marked regression in lung cancer progression, evidenced by macroscopic, PET/CT imaging and histological studies, concomitant with a greatly extended overall survival. Activin-A’s anti-tumor effects were associated with increased infiltration of CD4+ T effector cells in lung tumors and decreased frequencies of Foxp3+ Treg and myeloid derived suppressor cells. Moreover, activin-A treatment significantly decreased the expression of several immune checkpoint inhibitors among lung TILs. Mechanistic studies demonstrated that disruption of its signaling on CD4+ T cells, resulted in enhanced tumor progression accompanied by diminished effector responses and heightened percentages of Foxp3+ Treg cells and immune checkpoint inhibitors. Furthermore, CD4+ T cells from CD4/ALK4-KO mice exhibited impaired T cell proliferation capacity compared to CD4+ T cells obtained from healthy mice, indicative of an exhausted phenotype. Therapeutic administration of CD4+ T cell obtained from murine lung tumors and treated ex vivo with activin-A resulted in delayed formation of lung tumors accompanied by enhanced anti-tumor T-cell mediated immune responses.
In our translational studies, ex vivo administration of activin-A on tumor infiltrating leukocytes isolated from human lung cancer specimens resulted in the enhancement of an effector Th cell profile on CD4+ T cells, as evidenced by upregulation of TBX21, GATA3 and RORC. Notably, activin-A-treated CD4+ T cells were less able to suppress the proliferation of autologous naive CD4+ T cells. Additionally, we observed upregulation of TBX21, IRF4, GZMB and PRF1 in CD8+ T cells, upon ex vivo activin-A administration, suggesting that activin-A could be involved in the enhancement of the effector functions of tumor infiltrating CD8+ T cells.
To conclude, our studies reveal a novel role for activin-A in enhancing anti-tumor T cell-mediated responses that may be beneficial in the combat against lung cancer.