Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma
Introduction Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we e...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000987.full |
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| author | Valerie Chew Tony Kiat Hon Lim David Tai Su Pin Choo Joe Yeong Jeffrey Chun Tatt Lim Bernett Lee Huihua Li Sahil Saraf Han Chong Toh Benedict Tan Harry Ho Man Ng Ren Yuan Lee Siting Goh Isabel Shu Ying Tay Xinru Lim Sherlly Lim Bijin Au Josh Jie Hua Loh John Edward Connolly Tracy Loh Wei Qiang Leow Joycelyn Jie Xin Lee Fabio Malavasi Ser Yee Lee Pierce Chow Evan W Newell |
| author_facet | Valerie Chew Tony Kiat Hon Lim David Tai Su Pin Choo Joe Yeong Jeffrey Chun Tatt Lim Bernett Lee Huihua Li Sahil Saraf Han Chong Toh Benedict Tan Harry Ho Man Ng Ren Yuan Lee Siting Goh Isabel Shu Ying Tay Xinru Lim Sherlly Lim Bijin Au Josh Jie Hua Loh John Edward Connolly Tracy Loh Wei Qiang Leow Joycelyn Jie Xin Lee Fabio Malavasi Ser Yee Lee Pierce Chow Evan W Newell |
| author_sort | Valerie Chew |
| collection | DOAJ |
| description | Introduction Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC.Methods Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis.Results IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB.Conclusions A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC. |
| format | Article |
| id | doaj-art-63bba1dbcae64136851847771b46dfaf |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-63bba1dbcae64136851847771b46dfaf2024-11-09T23:50:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000987Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinomaValerie Chew0Tony Kiat Hon Lim1David Tai2Su Pin Choo3Joe Yeong4Jeffrey Chun Tatt Lim5Bernett Lee6Huihua Li7Sahil Saraf8Han Chong Toh9Benedict Tan10Harry Ho Man Ng11Ren Yuan Lee12Siting Goh13Isabel Shu Ying Tay14Xinru Lim15Sherlly Lim16Bijin Au17Josh Jie Hua Loh18John Edward Connolly19Tracy Loh20Wei Qiang Leow21Joycelyn Jie Xin Lee22Fabio Malavasi23Ser Yee Lee24Pierce Chow25Evan W Newell26Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore2 Department of Pathology, Singapore General Hospital, Singapore10 Division of Medical Oncology, National Cancer Centre Singapore, SingaporeDivision of Medical Oncology, National Cancer Centre Singapore, Singapore2 Division of Pathology, Singapore General Hospital, Singapore13 Institute of Molecular and Cell Biology, Integrative Biology for Theranostics Lab, Agency for Science Technology and Research (A*STAR), Singapore5Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore4 Center for Quantitative Medicine, Duke-NUS Medical School, Singapore2 Division of Pathology, Singapore General Hospital, Singapore8National Cancer Centre Singapore, Singapore, SingaporeExercise is Medicine Singapore, Singapore1 Duke-NUS Medical School, Singapore2 Division of Pathology, Singapore General Hospital, Singapore2 Division of Pathology, Singapore General Hospital, Singapore4 Temasek Polytechnic, Singapore5 Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore1 Institute of Molecular and Cell Biology, Agency of Science, Technology and Research (A*STAR), Singapore5 Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore2 Division of Pathology, Singapore General Hospital, Singapore5 Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore2 Division of Pathology, Singapore General Hospital, Singapore2 Division of Pathology, Singapore General Hospital, Singapore10 Division of Medical Oncology, National Cancer Centre Singapore, Singapore11 Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Torino, Torino, Italy1 Duke-NUS Medical School, SingaporeSingHeath Duke-NUS Global Health Institute, Singapore6 Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), SingaporeIntroduction Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC.Methods Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis.Results IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB.Conclusions A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.https://jitc.bmj.com/content/8/2/e000987.full |
| spellingShingle | Valerie Chew Tony Kiat Hon Lim David Tai Su Pin Choo Joe Yeong Jeffrey Chun Tatt Lim Bernett Lee Huihua Li Sahil Saraf Han Chong Toh Benedict Tan Harry Ho Man Ng Ren Yuan Lee Siting Goh Isabel Shu Ying Tay Xinru Lim Sherlly Lim Bijin Au Josh Jie Hua Loh John Edward Connolly Tracy Loh Wei Qiang Leow Joycelyn Jie Xin Lee Fabio Malavasi Ser Yee Lee Pierce Chow Evan W Newell Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma |
| title_full | Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma |
| title_fullStr | Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma |
| title_full_unstemmed | Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma |
| title_short | Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma |
| title_sort | immunohistochemical scoring of cd38 in the tumor microenvironment predicts responsiveness to anti pd 1 pd l1 immunotherapy in hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/8/2/e000987.full |
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