The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC
Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treat...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | JTO Clinical and Research Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364322000972 |
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| author | Hiroaki Kanemura, MD, MPH Hidetoshi Hayashi, MD, PhD Shuta Tomida, PhD Junko Tanizaki, MD, PhD Shinichiro Suzuki, MD, PhD Yusuke Kawanaka, MD Asuka Tsuya, MD Yasushi Fukuda, MD Hiroyasu Kaneda, MD, PhD Keita Kudo, MD Takayuki Takahama, MD, PhD Ryosuke Imai, MD Koji Haratani, MD, PhD Yasutaka Chiba, PhD Tomoyuki Otani, MD Akihiko Ito, MD, PhD Kazuko Sakai, PhD Kazuto Nishio, MD, PhD Kazuhiko Nakagawa, MD, PhD |
| author_facet | Hiroaki Kanemura, MD, MPH Hidetoshi Hayashi, MD, PhD Shuta Tomida, PhD Junko Tanizaki, MD, PhD Shinichiro Suzuki, MD, PhD Yusuke Kawanaka, MD Asuka Tsuya, MD Yasushi Fukuda, MD Hiroyasu Kaneda, MD, PhD Keita Kudo, MD Takayuki Takahama, MD, PhD Ryosuke Imai, MD Koji Haratani, MD, PhD Yasutaka Chiba, PhD Tomoyuki Otani, MD Akihiko Ito, MD, PhD Kazuko Sakai, PhD Kazuto Nishio, MD, PhD Kazuhiko Nakagawa, MD, PhD |
| author_sort | Hiroaki Kanemura, MD, MPH |
| collection | DOAJ |
| description | Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (−0.18 versus −0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056 |
| first_indexed | 2024-04-13T09:29:28Z |
| format | Article |
| id | doaj.art-dbb20eead9094769a8713112200e34c2 |
| institution | Directory Open Access Journal |
| issn | 2666-3643 |
| language | English |
| last_indexed | 2024-04-13T09:29:28Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JTO Clinical and Research Reports |
| spelling | doaj.art-dbb20eead9094769a8713112200e34c22022-12-22T02:52:20ZengElsevierJTO Clinical and Research Reports2666-36432022-08-0138100373The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLCHiroaki Kanemura, MD, MPH0Hidetoshi Hayashi, MD, PhD1Shuta Tomida, PhD2Junko Tanizaki, MD, PhD3Shinichiro Suzuki, MD, PhD4Yusuke Kawanaka, MD5Asuka Tsuya, MD6Yasushi Fukuda, MD7Hiroyasu Kaneda, MD, PhD8Keita Kudo, MD9Takayuki Takahama, MD, PhD10Ryosuke Imai, MD11Koji Haratani, MD, PhD12Yasutaka Chiba, PhD13Tomoyuki Otani, MD14Akihiko Ito, MD, PhD15Kazuko Sakai, PhD16Kazuto Nishio, MD, PhD17Kazuhiko Nakagawa, MD, PhD18Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; Corresponding author. Address for correspondence: Hidetoshi Hayashi, MD, PhD, Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; Department of Medical Oncology, Kishiwada City Hospital, Osaka, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; Department of Medical Oncology, Kishiwada City Hospital, Osaka, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; Department of Medical Oncology, Kishiwada City Hospital, Osaka, JapanDepartment of Medical Oncology, Izumi City General Hospital, Osaka, JapanDepartment of Respiratory Medicine, Kurashiki Central Hospital, Okayama, JapanDepartment of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, JapanDepartment of Thoracic Medical Oncology, National Hospital Organization Osaka Minami Medical Center, Osaka, JapanDepartment of Medical Oncology, Kindai University Nara Hospital, Nara, JapanDepartment of Pulmonary Medicine, Thoracic Center, St. Luke’s International Hospital, Tokyo, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka, JapanClinical Research Center, Kindai University Hospital, Osaka, JapanDepartment of Pathology, Kindai University Faculty of Medicine, Osaka, JapanDepartment of Pathology, Kindai University Faculty of Medicine, Osaka, JapanDepartment of Genome Biology, Kindai University Faculty of Medicine, Osaka, JapanDepartment of Genome Biology, Kindai University Faculty of Medicine, Osaka, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka, JapanIntroduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (−0.18 versus −0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056http://www.sciencedirect.com/science/article/pii/S2666364322000972Small cell lung cancerImmunotherapyTumor-infiltrating lymphocyteTumor mutation burdenNeoantigen |
| spellingShingle | Hiroaki Kanemura, MD, MPH Hidetoshi Hayashi, MD, PhD Shuta Tomida, PhD Junko Tanizaki, MD, PhD Shinichiro Suzuki, MD, PhD Yusuke Kawanaka, MD Asuka Tsuya, MD Yasushi Fukuda, MD Hiroyasu Kaneda, MD, PhD Keita Kudo, MD Takayuki Takahama, MD, PhD Ryosuke Imai, MD Koji Haratani, MD, PhD Yasutaka Chiba, PhD Tomoyuki Otani, MD Akihiko Ito, MD, PhD Kazuko Sakai, PhD Kazuto Nishio, MD, PhD Kazuhiko Nakagawa, MD, PhD The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC JTO Clinical and Research Reports Small cell lung cancer Immunotherapy Tumor-infiltrating lymphocyte Tumor mutation burden Neoantigen |
| title | The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
| title_full | The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
| title_fullStr | The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
| title_full_unstemmed | The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
| title_short | The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
| title_sort | tumor immune microenvironment and frameshift neoantigen load determine response to pd l1 blockade in extensive stage sclc |
| topic | Small cell lung cancer Immunotherapy Tumor-infiltrating lymphocyte Tumor mutation burden Neoantigen |
| url | http://www.sciencedirect.com/science/article/pii/S2666364322000972 |
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