Jiaqiang Ma

<h3>Background</h3> CD8⁺ T cells differentiate into exhausted status within tumors, including hepatocellular carcinoma (HCC), which constitutes a solid barrier to effective anti-tumor immunity. A detailed characterization of exhausted T cells and their prognostic value in HCC is lacking. <h3>Methods</h3> We collected fresh tumor tissues with adjacent non-tumor liver tissues and blood specimens of 56 HCC patients, as well as archived samples from two independent cohorts of HCC patients (<i>n</i> = 358 and <i>n</i> = 254), who underwent surgical resection. Flow cytometry and multiplex immunostaining were used to characterize CD8⁺ T cells. Patient prognosis was evaluated by Kaplan-Meier analysis and Cox regression analysis. <h3>Results</h3> CD8⁺ T cells were classified into three distinct subpopulations: PD1^Hi, PD1^Int and PD1⁻. PD1^Hi CD8⁺ T cells were significantly enriched in tumor compared to adjacent non-tumor liver tissues. PD1^Hi CD8⁺ T cells highly expressed exhaustion-related inhibitory receptors (TIM3, CTLA-4, etc.) and transcription factors (Eomes, BATF, etc.). In addition, PD1^Hi CD8⁺ T cells expressed low levels of cytotoxic molecules and displayed a compromised capacity to produce pro-inflammatory cytokines while the expression of anti-inflammatory IL-10 was up-regulated following mitotic stimulation. Furthermore, PD1^Hi CD8⁺ T cells shared features with tissue resident memory T cells and were also characterized in an aberrantly activated status with an apoptosis-prone potential. In two independent cohorts of HCC patients (<i>n</i> = 358 and <i>n</i> = 254), we demonstrated that PD1^Hi or TIM3⁺PD1^Hi CD8⁺ T cells were significantly correlated with poor prognosis, and the latter was positioned in close proximity to PD-L1⁺ tumor associated macrophages. <h3>Conclusion</h3> The current study unveils the unique features of PD1^Hi CD8⁺ exhausted T cells in HCC, and also suggests that exhausted T cells could act as a biomarker to select the most care-demanding patients for tailored therapies.

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.