CXCR5⁺ CD8⁺ T cells potently infiltrate pancreatic tumors and present high functionality

Despite continued improvement in conventional therapy, pancreatic cancer continues to be one of the deadliest tumors worldwide with abysmal 5-year survival rate. New immunotherapeutic strategies that aim at improving antitumor cytotoxic CD8⁺ T cell responses are being developed in solid tumors. To assist the development of immunotherapies, we investigated the CD8⁺ T cells in pancreatic cancer patients. Compared to healthy individuals, pancreatic cancer patients presented a significant enrichment in the frequency of CD8⁺CXCR5⁺ T cells. In the tumor microenvironment, the frequencies of CD8⁺CXCR5⁺ T cells were further increased. In most cases, over half of tumor-infiltrating CD8⁺ T cells were CD8⁺CXCR5⁺ T cells. Compared to the circulating population, the tumor-infiltrating CD8⁺CXCR5⁺ T cells expressed higher levels of PD-1 and TIM-3. Functional analyses demonstrated that upon CD3/CD28 activation, the percentages of TNF-expressing and IFN-γ-expressing cells in CD8⁺CXCR5⁺ T cells were significantly higher than that in CD8⁺CXCR5^- T cells. CD8⁺CXCR5⁺ T cells also presented enhanced cytotoxicity than CD8⁺CXCR5^- T cells. Upon PD-1 and TIM-3 blockade, the functions of CD8⁺CXCR5⁺ T cells were further improved. The disease-free survival of pancreatic cancer patients following tumor resection was positively correlated with the frequencies of circulating and tumor-infiltrating CD8⁺CXCR5⁺ T cells. Together, our study identified that CD8⁺CXCR5⁺ T cells were a potent subset of CD8⁺ T cells that were highly enriched in pancreatic cancer patients and could respond to anti-PD-1/anti-TIM-3 blockade by further upregulation in function.