Dynamic changes in the immune infiltrate within hepatocellular carcinoma tumor correlate with response to PD-1 blockade.

Abstract

e15644 Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in men worldwide, and is the most rapidly rising cause of cancer mortality in the US. Patients with resectable disease experience high rates of locoregional recurrence, and there are few effective systemic treatment options available. PD-1 blockade was recently approved for 2nd line therapy, and there are promising response rates seen in the 1st-line setting. However, only 20% of patients achieve significant response, thus we must investigate further the tumor-immune microenvironment to understand how to better modulate the immune system in this highly immunosuppressive organ. Methods: We used mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to study protein and transcriptomics of untreated tumor and tumor adjacent tissue, on a single-cell level. Results: Paired CyTOF analysis of 10 tumor lesions/adjacent tissues identified a significant increase in frequency of CD4+ T cells and T regulatory cells, a significant decrease in NK cells and neutrophils, and no difference in CD8+ T cells, macrophages, or dendritic cells (DCs) in the tumor microenvironment compared to the adjacent liver tissue. We also analyzed four patients who received nivolumab and subsequently went on to have their liver tumors resected; two out of the four patients treated had near-complete necrosis of their tumors (radiographically and histologically). Of note, the tumors of the two patients with significant pathologic response contained a significantly higher number of CD103+ tissue resident CD8+ and CD4+ T cells, compared to adjacent tissue. Moreover, activated CD8+ T cells (TIGIT+, PD-1+, TIM3+, and/or CD38+) were significantly higher in the tumor of nivolumab responders, indicating a tumor-specific response. We will also present single cell transcriptomic analyses of T cell and myeloid populations in responders and non-responders. Interestingly, high levels of nivolumab were detected on PD-1+ T cells in the tumor in all 4 patients; we will discuss transcriptional differences between nivolumab-targeted T cells in responders and non-responder patients. Conclusions: Based on this preliminary data we will be opening a clinical trial of neoadjuvant PD-1 blockade in HCC (NCT# pending) in March 2019.