Chia-Lang Hsu1,2,3, Da-Liang Ou2, Li-Yuan Bai4, Chia-Wei Chen2, Li Lin2, Shiu-Feng Huang5, Ann-Lii Cheng6,7,8, Yung-Ming Jeng9, Chiun Hsu2,6,7. 1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. 2. Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. 3. Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan. 4. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan. 5. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan. 6. National Taiwan University Cancer Center, Taipei, Taiwan. 7. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 8. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 9. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
Abstract
BACKGROUND: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. OBJECTIVES: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). METHODS: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. RESULTS: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8+LAG3+ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. CONCLUSIONS: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
BACKGROUND: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. OBJECTIVES: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). METHODS: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. RESULTS: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8+LAG3+ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. CONCLUSIONS: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
Authors: Patrick A Ott; Yung-Jue Bang; Sarina A Piha-Paul; Albiruni R Abdul Razak; Jaafar Bennouna; Jean-Charles Soria; Hope S Rugo; Roger B Cohen; Bert H O'Neil; Janice M Mehnert; Juanita Lopez; Toshihiko Doi; Emilie M J van Brummelen; Razvan Cristescu; Ping Yang; Kenneth Emancipator; Karen Stein; Mark Ayers; Andrew K Joe; Jared K Lunceford Journal: J Clin Oncol Date: 2018-12-13 Impact factor: 44.544
Authors: Christian U Blank; W Nicholas Haining; Werner Held; Patrick G Hogan; Axel Kallies; Enrico Lugli; Rachel C Lynn; Mary Philip; Anjana Rao; Nicholas P Restifo; Andrea Schietinger; Ton N Schumacher; Pamela L Schwartzberg; Arlene H Sharpe; Daniel E Speiser; E John Wherry; Benjamin A Youngblood; Dietmar Zehn Journal: Nat Rev Immunol Date: 2019-09-30 Impact factor: 53.106
Authors: Itay Tirosh; Benjamin Izar; Sanjay M Prakadan; Marc H Wadsworth; Daniel Treacy; John J Trombetta; Asaf Rotem; Christopher Rodman; Christine Lian; George Murphy; Mohammad Fallahi-Sichani; Ken Dutton-Regester; Jia-Ren Lin; Ofir Cohen; Parin Shah; Diana Lu; Alex S Genshaft; Travis K Hughes; Carly G K Ziegler; Samuel W Kazer; Aleth Gaillard; Kellie E Kolb; Alexandra-Chloé Villani; Cory M Johannessen; Aleksandr Y Andreev; Eliezer M Van Allen; Monica Bertagnolli; Peter K Sorger; Ryan J Sullivan; Keith T Flaherty; Dennie T Frederick; Judit Jané-Valbuena; Charles H Yoon; Orit Rozenblatt-Rosen; Alex K Shalek; Aviv Regev; Levi A Garraway Journal: Science Date: 2016-04-08 Impact factor: 47.728
Authors: Peng Jiang; Shengqing Gu; Deng Pan; Jingxin Fu; Avinash Sahu; Xihao Hu; Ziyi Li; Nicole Traugh; Xia Bu; Bo Li; Jun Liu; Gordon J Freeman; Myles A Brown; Kai W Wucherpfennig; X Shirley Liu Journal: Nat Med Date: 2018-08-20 Impact factor: 53.440
Authors: Julian L Goggi; Boominathan Ramasamy; Yun Xuan Tan; Siddesh V Hartimath; Jun Rong Tang; Peter Cheng; Rasha Msallam; Ann-Marie Chacko; You Yi Hwang; Edward G Robins Journal: Mol Imaging Date: 2021-12-09 Impact factor: 3.250