CXCR5+CD8+ T cells could induce the death of tumor cells in HBV-related hepatocellular carcinoma.

The follicular CXCR5+CD8+ T cells have recently emerged as a critical cell type in mediating peripheral tolerance as well as antiviral immune responses during chronic infections. In this study, we investigated the function of CXCR5+CD8+ T cells in HBV-related hepatocellular carcinoma patients. Compared to CXCR5-CD8+ T cells, CXCR5+CD8+ T cells presented elevated PD-1 expression but reduced Tim-3 and CTLA-4 expression. Upon anti-CD3/CD28 stimulation, CXCR5+CD8+ T cells demonstrated higher proliferation potency than CXCR5-CD8+ T cells, especially after PD-1 blockade. CXCR5+CD8+ T cells also demonstrated significantly higher granzyme B synthesis and release, as well as higher level of degranulation. Tumor cells were more readily eliminated by CXCR5+CD8+ T cells than by CXCR5-CD8+ T cells. Interestingly, we found that B cells were more resistant to CXCR5+CD8+ T cell-mediated killing than tumor cells, possibly through IL-10-mediated protection. In addition, the CXCR5+CD8+ T cell-mediated cytotoxic effects on tumor cells could be significantly enhanced by PD-L1 blockade. Together, we presented that in patients with in HBV-related hepatocellular carcinoma, CXCR5+CD8+ T cells could mediate tumor cell death more potently than the CXCR5-CD8+ T cells in vitro while the autologous B cells were protected.

Reactivity toward Bifidobacterium longum and Enterococcus hirae demonstrate robust CD8+ T cell response and better prognosis in HBV-related hepatocellular carcinoma.

Recent studies suggest that several bacterial species are involved in tumor immunosurveillance and antitumor immunity. The role of bacteria in immune responses in HBV-related hepatocellular carcinoma (HCC) patients is still unknown. In this study, we examined the bacteria-reactive CD8+ T cell response in patients with HBV-related HCC. We found that circulating CD8+ T cells from healthy individuals demonstrated minimal or zero specificity toward a series of commensals and bacteria previously associated with antitumor effects, including Escherichia coli, Enterococcus faecium, Bifidobacterium longum, Bacteroides fragilis, and Enterococcus hirae. In contrast, the circulating CD8+ T cells from HBV-related HCC patients presented significantly elevated bacteria-reactive responses, albeit with high variations among different HCC individuals. Reactivity toward bacteria was also identified in tumor-infiltrating CD8+ T cells. These bacteria-reactive responses were not primarily induced by TLR ligand, but were dependent on the presence of antigen-presenting monocytes, and were MHC class I-restricted. Interestingly, we observed that the CD8+ T cell-to-Foxp3+ regulatory T cell ratio was positively correlated with the proportions of Bifidobacterium longum-reactive and Enterococcus hirae-reactive CD8+ T cells, while the frequency of PD-1+ CD8+ T cells was negatively correlated with the frequency of Enterococcus hirae-reactive CD8+ T cells. Furthermore, the disease-free survival time of HCC patients after tumor resection was positively correlated with the frequencies of Bifidobacterium longum-reactive and Enterococcus hirae-reactive CD8+ T cells. Together, these results suggested that certain bacterial species might present valuable antitumor effects.

Preferential Tim-3 expression on Treg and CD8(+) T cells, supported by tumor-associated macrophages, is associated with worse prognosis in gastric cancer.

While infection with H. pylori is a strong risk factor for gastric cancer, most H. pylori-colonized individuals, even those with the high-risk CagA(+)VacA(+) strain, remain asymptomatic over their lifetime. We hypothesized that the discordant outcomes were due to differences in the host immune responses. Previously, Tim-3-mediated immune modulation was observed in H. pylori-challenged mice. In this study, we compared Tim-3-related responses in CagA(+)VacA(+) H. pylori-infected asymptomatic individuals and H. pylori-associated gastric adenocarcinoma patients. We showed that compared to H. pylori-uninfected individuals, both H. pylori-infected asymptomatic and gastric cancer patients upregulated Tim-3 overall. However, the Tim-3 upregulation was enriched on Th1 cells in asymptomatic patients and on Treg and CD8(+) T cells in gastric cancer patients, with respective differences in T cell subset functions. In gastric cancer patients, high Tim-3 expression on Treg and CD8(+) T cells, but not on Th1 cells, was associated with worse prognosis. H. pylori-antigen presentation by tumor-associated macrophages upregulated Tim-3 expression more effectively than by blood monocyte-derived macrophages in vitro. The upregulation of Tim-3 in vitro depended on the concentration of H. pylori antigen but not on whether the cells were from asymptomatic or cancer patients. These data suggest that the discrepancy in Tim-3 upregulation in asymptomatic and cancer subjects is induced by cancer but not the other way around. Once gastric cancer is developed, Tim-3 expression is associated with worse prognosis.