Project description:Overcoming CD8+ T cell "exhaustion" is critical in cancer immunotherapy. Intra-tumor CD8+ T cells contain stem-like (Texprog) and terminally differentiated (Texterm) subpopulations that mediate the persistence and potency of anti-tumor responses, respectively. How extrinsic signals via transcription factors control these two subsets are unclear. Previously, Bcl6 was shown to be selectively expressed by Texprog cells and promote their generation in chronic infection. Here, we found that in cancer, Bcl6 deficiency impacted, not the generation, but rather the persistence of Texprog cells, thus abrogating long-term tumor control. Bcl6 expression in CD8+ T cells is reciprocally regulated by TGF-?-SMAD2 and IL-2-STAT5 signaling pathways. Blimp1, regulated by IL-2 signaling, potently inhibited Bcl6 expression and its transcriptional activities; Prdm1 deficiency greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-?-Bcl6 and IL-2-Blimp1 antagonistic pathways in regulation of anti-tumor CD8+ T cells, which benefits cancer immunotherapy.
Project description:Overcoming CD8+ T cell "exhaustion" is critical in cancer immunotherapy. Intra-tumor CD8+ T cells contain stem-like (Texprog) and terminally differentiated (Texterm) subpopulations that mediate the persistence and potency of anti-tumor responses, respectively. How extrinsic signals via transcription factors control these two subsets are unclear. Previously, Bcl6 was shown to be selectively expressed by Texprog cells and promote their generation in chronic infection. Here, we found that in cancer, Bcl6 deficiency impacted, not the generation, but rather the persistence of Texprog cells, thus abrogating long-term tumor control. Bcl6 expression in CD8+ T cells is reciprocally regulated by TGF-?-SMAD2 and IL-2-STAT5 signaling pathways. Blimp1, regulated by IL-2 signaling, potently inhibited Bcl6 expression and its transcriptional activities; Prdm1 deficiency greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-?-Bcl6 and IL-2-Blimp1 antagonistic pathways in regulation of anti-tumor CD8+ T cells, which benefits cancer immunotherapy.
