Deep profiling and in situ mapping of human hepatocellular carcinoma (HCC) immune milieu: Where are the origins of CD103+ resident memory-like T cells and the clinical implication?
Joe Yeong1,2, Yang Cheng1, Karen Teng1, Etienne Becht1, Chen Jinmiao1, Bavani Guna1, Harsimran Singh1, Tan Lingqiao1, Zhai Weiwei3, Antonio Bertoletti1,4, Seng Gee Lim5, Han Chong Toh6, Pierce Chow6, Tony Kiat Hon Lim2, Su Pin Choo5, Evan W. Newell1*
1Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN); 2Division of Pathology, Singapore General Hospital; 3Genomic Institute of Singapore; 4Duke-NUS Medical School, 5National University Health System, 6National Cancer Centre Singapore
HBV is the single most common cause of HCC that accounts for approximately 50% of all HCC cases worldwide, especially in developing countries. Currently, about 5% of the world's population (240-350 million people) is chronically infected by HBV. We combined two state-of-the-art technologies to study HCC patient cohorts; A) mass cytometry and highly multiplexed peptide-MHC tetramer staining for deep profiling of antigen-specific T cell populations and B) high-throughput multiplex Immunohistochemistry (m-IHC) for deep mapping of the distribution of such T cell populations and their interaction with other immune subsets as well as the structures in the liver microenvironment such as sinusoids, vessels, portal tracts, liver lobules and tumor islands. Following up on our previous study (Wong et al. Immunity 2016) that identified and profiled CD69+CD103+ resident T and NK cell populations in liver samples obtained from healthy donors, we compared the features of these and other resident lymphocyte populations derived from adjacent normal liver (near tumor) vs. tumor vs. normal liver far from tumor of HCC patients. We found that CD103+ CD8+ T cells can be subclassified into two distinct populations, 1) bona fide resident memory T cells and 2) induced exhausted subset. Subsequently we also identified that the in situ geographical changes in the microenvironment and abundances of such subsets are associated with clinicopathological parameters and prognosis of the patients in an opposite manner. Ongoing studies aim to compare the characteristics of these cells derived from HCC patients treated with Nivolumab (anti-PD-1 therapy) and Sorafenib (standard-of-care) to identify T cell based biomarkers to predict the responsiveness of such therapies.