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361 Heterogeneity of PD-1hi T cells associates with response to PD-1 blockade in hepatocellular carcinoma
  1. Assaf Magen,
  2. Assaf Magen,
  3. Pauline Hamon,
  4. Myron Schwartz,
  5. Thomas Marron,
  6. Alice Kamphorst and
  7. Miriam Merad
  1. MSSM, New York, NY, USA


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 the first line setting this achieves significant clinical response in about 25% of hepatocellular carcinoma (HCC) patients. We hypothesize that phenotypic diversity of tumor infiltrating T cells can explain, at least partially, the disparate clinical responses to immunotherapy.

Methods Here, we analyze the molecular diversity of T cells in tumor, adjacent tissue and tumor-draining lymph node (dLN) by single-cell RNA sequencing of tissue from 23 patients with early stage HCC treated by neoadjuvant PD-1 blockade (NCT03916627).

Results We identify distinct subsets of PD-1hi T cells with varying degrees of exhaustion and effector gene programs. Compared to parallel analysis of untreated HCC tumors, we observed that PD-1 blockade resulted in expansion of PD-1hi T cells in the tumor, regardless of clinical response. PD-1hi T cells subsets were highly clonal and enriched in the tumor compared to adjacent tissue, suggesting specificity to tumor antigens. Remarkably, within the PD-1hi T cell population we find an association between specific transcriptomic phenotype that correlates with response to PD-1 blockade. Using T cell receptor (TCR) sequencing to study the differentiation patterns between T cell states, we found that clonotypes present among expanded PD-1hi T cells were also found in CD8 effector cells; these data identify characteristic clonally related T cell populations that are enriched in clinical responders. Furthermore, we find that dLN harbor clonotypes of PD-1hi T cells expanded in tumor. In the dLN, these potentially tumor-specific T cells have features of activation and exhaustion suggesting a continuous role of dLN in anti-tumor responses. This study suggests a link between particular PD-1hi T cell subsets and responsiveness to PD-1 blockade.

Conclusions These results will be corroborated with 8 additional patient samples in which we will further analyze the role of tumor-specific T cells in dLN. Furthermore, our ongoing sequencing of pre-treatment lesions will enable monitoring of T cell clonal expansion, and additionally transcriptomic characterization of these samples will be correlated with post-treatment T cell programs to test predictive potential of baseline lymphoid phenotype. Correlations of these phenotypes with response to PD-1 blockade will allow for validation of predictive biomarkers, and characterizing these T cell programs in the dLN and the tumor microenvironment will enable superior and personalized therapeutic interventions.

Ethics Approval Samples of tumor and non-involved liver were obtained from surgical specimens of patients undergoing resection at Mount Sinai Hospital (New York, NY) after obtaining informed consent in accordance with a protocol reviewed and approved by the Institutional Review Board at the Icahn School of Medicine at Mount Sinai (RUTH Human Subjects Electronic Submission System 18-00407 and 20-04150) and in collaboration with the Biorepository and Department of Pathology.

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