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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356091/ https://www.ncbi.nlm.nih.gov/pubmed/35941997 http://dx.doi.org/10.1016/j.jtocrr.2022.100373 |
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author | Kanemura, Hiroaki Hayashi, Hidetoshi Tomida, Shuta Tanizaki, Junko Suzuki, Shinichiro Kawanaka, Yusuke Tsuya, Asuka Fukuda, Yasushi Kaneda, Hiroyasu Kudo, Keita Takahama, Takayuki Imai, Ryosuke Haratani, Koji Chiba, Yasutaka Otani, Tomoyuki Ito, Akihiko Sakai, Kazuko Nishio, Kazuto Nakagawa, Kazuhiko |
author_facet | Kanemura, Hiroaki Hayashi, Hidetoshi Tomida, Shuta Tanizaki, Junko Suzuki, Shinichiro Kawanaka, Yusuke Tsuya, Asuka Fukuda, Yasushi Kaneda, Hiroyasu Kudo, Keita Takahama, Takayuki Imai, Ryosuke Haratani, Koji Chiba, Yasutaka Otani, Tomoyuki Ito, Akihiko Sakai, Kazuko Nishio, Kazuto Nakagawa, Kazuhiko |
author_sort | Kanemura, Hiroaki |
collection | PubMed |
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 |
format | Online Article Text |
id | pubmed-9356091 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-93560912022-08-07 The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC Kanemura, Hiroaki Hayashi, Hidetoshi Tomida, Shuta Tanizaki, Junko Suzuki, Shinichiro Kawanaka, Yusuke Tsuya, Asuka Fukuda, Yasushi Kaneda, Hiroyasu Kudo, Keita Takahama, Takayuki Imai, Ryosuke Haratani, Koji Chiba, Yasutaka Otani, Tomoyuki Ito, Akihiko Sakai, Kazuko Nishio, Kazuto Nakagawa, Kazuhiko JTO Clin Res Rep Original Article 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 Elsevier 2022-07-01 /pmc/articles/PMC9356091/ /pubmed/35941997 http://dx.doi.org/10.1016/j.jtocrr.2022.100373 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Kanemura, Hiroaki Hayashi, Hidetoshi Tomida, Shuta Tanizaki, Junko Suzuki, Shinichiro Kawanaka, Yusuke Tsuya, Asuka Fukuda, Yasushi Kaneda, Hiroyasu Kudo, Keita Takahama, Takayuki Imai, Ryosuke Haratani, Koji Chiba, Yasutaka Otani, Tomoyuki Ito, Akihiko Sakai, Kazuko Nishio, Kazuto Nakagawa, Kazuhiko The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
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 | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356091/ https://www.ncbi.nlm.nih.gov/pubmed/35941997 http://dx.doi.org/10.1016/j.jtocrr.2022.100373 |
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