361 Heterogeneity of PD-1hi T cells associates with response to PD-1 blockade in hepatocellular carcinoma

Background Blockade of the PD-1 pathway is a therapeutic strategy to reinvigorate T cell responses against tumors, and when combined with other biologic therapies in first line setting this achieves significant clinical response about 25% hepatocellular carcinoma (HCC) patients. We hypothesize that phenotypic diversity tumor infiltrating cells can explain, at least partially, disparate immunotherapy. Methods Here, we analyze molecular tumor, adjacent tissue tumor-draining lymph node (dLN) by single-cell RNA sequencing from 23 patients early stage HCC treated neoadjuvant blockade ( NCT03916627 ). Results identify distinct subsets PD-1hi varying degrees exhaustion effector gene programs. Compared parallel analysis untreated observed resulted expansion regardless response. were highly clonal enriched compared tissue, suggesting specificity antigens. Remarkably, within population find an association between specific transcriptomic phenotype correlates blockade. Using receptor (TCR) study differentiation patterns states, found clonotypes present among expanded also CD8 cells; these data characteristic clonally related populations are responders. Furthermore, dLN harbor tumor. In dLN, potentially tumor-specific have features activation continuous role anti-tumor responses. This suggests link particular responsiveness Conclusions These results will be corroborated 8 additional patient samples which further dLN. our ongoing pre-treatment lesions enable monitoring expansion, additionally characterization correlated post-treatment programs test predictive potential baseline lymphoid phenotype. Correlations phenotypes allow for validation biomarkers, characterizing microenvironment superior personalized interventions. Ethics Approval Samples non-involved liver obtained surgical specimens undergoing resection Mount Sinai Hospital (New York, NY) after obtaining informed consent accordance protocol reviewed approved Institutional Review Board Icahn School Medicine (RUTH Human Subjects Electronic Submission System 18-00407 20-04150) collaboration Biorepository Department Pathology.