[2019 Fall Life Sciences & IBB Seminar]
▶Subject: Heterogeneous T cell exhaustion in cancers and its implications in cancer immunotherapy
▶Speaker: Prof. Su-Hyung Park (KAIST)
▶Date: 4:30PM/Nov. 15(Fri.)/2019
▶Place: Auditorium(1F), Postech Biotech Center
T-cell exhaustion, or an impaired capacity to secrete cytokines and proliferate with overexpression of immune checkpoint receptors, occurs during chronic viral infections but has also been observed in tumors. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and several agents targeting PD-1, PD-L1, and CTLA-4 have been approved for many types of cancer. However, the therapeutic efficacy of ICIs substantially varies among cancer types and patients, and only a limited proportion of cancer patients benefit clinically from ICIs. To improve the therapeutic efficacy of cancer treatments involving ICI, the mechanisms of response to ICIs and the heterogeneous pattern of immune checkpoint receptor expression need to be better understood. Here, we examined the heterogeneity of exhausted tumor-infiltrating CD8+ T cells (CD8+ TILs) by analyzing gene expression profiles, immunophenotypes, exhaustion-related transcription factors, and functional capacities using flow cytometry and RNA sequencing in hepatocellular carcinoma (HCC). We found HCC specimens to contain CD8+ TILs that express different levels of PD-1. PD-1hi cells expressed Tim-3 and Lag-3, and a low proportion was TCF-1+, T-bethi/eomeslo, and CD127+. HCCs with high proportions of PD-1hi CD8+ T cells express Tim-3 and/or Lag-3 and produce low levels of IFNG and TNF in response to anti-CD3. Incubation of these cells with antibodies against PD-1 and Tim-3 or Lag-3 further restore proliferation and production of cytokines; HCCs with high proportions of PD-1hi CD8+ TILs might be more susceptible to combined immune checkpoint blockade-based therapies. Moreover, as targeting co-stimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option, we also investigated co-stimulatory receptor expression on CD8+ TILs and its association with distinct T-cell activation features among exhausted CD8+ TILs. We found that 4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC and 4-1BB co-stimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.
▶Inquiry: Prof. You Jeong Lee (279-2359)