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Abstract

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. T-cell infiltration and/or the presence of PD-L1 in tumors may be used as indicators of clinical response; However, recent studies reported that preexisting tumor-specific T cells may have limited reinvigoration capacity. Therefore, evaluating status of T cells of tumor-adjacent area and its impact on the prognosis are very important. Here, we examined 117 surgical samples from HCC patients for infiltration of exhausted T cell (Tex) including CD4⁺-Tex, CD8<sup>+<sup>-Tex and regulatory T cell (FOXP3⁺-Treg) in tumor and adjacent tissue. CD3⁺CD45RO⁺T cells were sorted from adjacent area or tumor core, then the clusters and heterogeneity of T cells were further interrogated by single-cell RNA sequencing. As a result, we suggested that abundance or location of T cell subsets is differentially correlate with long-term clinical outcome of HCC. In contrast with CD4⁺T or CD4⁺-Tex, the infiltration of CD8⁺T or CD8⁺-Tex cells was closely linked to overall or recurrence-free survival. FOXP3⁺-Treg is more predictive of early recurrence. Single-cell transcriptional analysis demonstrates the composition of CD4⁺-Tex, CD8⁺-Tex, and FOXP3⁺-Treg is shifted in tumor and adjacent tissue. Molecular profiles including genes coding checkpoint receptors, effector molecules are distinct between CD4⁺-Tex, CD8⁺-Tex, though some common features of CD4⁺ and CD8⁺ T cell exhaustion are revealed. In conclusion, we underline the heterogeneity and clinical relevance of Tex cells in HCC patients. A better understanding of Tex is critical for HCC monitoring and treatment.