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

Abstract

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.