Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma

• Main Authors: Chuah, Samuel, Lee, Joycelyn, Song, Yuan, Kim, Hyung-Don, Wasser, Martin, Kaya, Neslihan A., Bang, Kyunghye, Lee, Yong Joon, Jeon, Seung Hyuck, Suthen, Sheena, A'Azman, Shamirah, Gien, Gerald, Lim, Chun Jye, Chua, Camillus, Sharifah Nur Hazirah, Lee, Hong Kai, Lim, Jia Qi, Lim, Tony K. H., Yeong, Joe, Chen, Jinmiao, Shin, Eui-Cheol, Albani, Salvatore, Zhai, Weiwei, Yoo, Changhoon, Liu, Haiyan, Choo, Su Pin, Tai, David, Chew, Valerie
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Biological sciences; Checkpoint Inhibitor; Immunoprofiling
• Online Access: https://hdl.handle.net/10356/162640
• Institution: Nanyang Technological University

Background & Aims: While immune checkpoint blockade (ICB) has shown promise in patients with hepatocellular carcinoma (HCC), it is associated with modest response rates and immune-related adverse events (irAEs) are common. In this study, we aimed to decipher immune trajectories and mechanisms of response and/or irAEs in patients with HCC receiving anti-programmed cell death 1 (anti-PD-1) therapy. Methods: Pre- and on-treatment peripheral blood samples (n = 60) obtained from 32 patients with HCC (Singapore cohort) were analysed by cytometry by time-of-flight and single-cell RNA sequencing, with flow cytometric validation in an independent Korean cohort (n = 29). Mechanistic validation was conducted by bulk RNA sequencing of 20 pre- and on-treatment tumour biopsies and using a murine HCC model treated with different immunotherapeutic combinations. Results: Single-cell analyses identified CXCR3+ CD8+ effector memory T (TEM) cells and CD11c+ antigen-presenting cells (APC) as associated with response (p = 0.0004 and 0.0255, respectively), progression-free survival (p = 0.00079 and 0.0015, respectively), and irAEs (p = 0.0034 and 0.0125, respectively) in anti-PD-1-treated patients with HCC. Type-1 conventional dendritic cells were identified as the specific APC associated with response, while 2 immunosuppressive CD14+ myeloid clusters were linked to reduced irAEs. Further analyses of CXCR3+ CD8+ TEM cells showed cell-cell interactions specific to response vs. irAEs, from which the anti-PD-1 and anti-TNFR2 combination was harnessed to uncouple these effects, resulting in enhanced response without increased irAEs in a murine HCC model. Conclusions: This study identifies early predictors of clinical response to anti-PD-1 ICB in patients with HCC and offers mechanistic insights into the immune trajectories of these immune subsets at the interface between response and toxicity. We also propose a new combination immunotherapy for HCC to enhance response without exacerbating irAEs.