The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC
© 2022 The Authors..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
JTO clinical and research reports - 3(2022), 8 vom: 21. Aug., Seite 100373 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kanemura, Hiroaki [VerfasserIn] |
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| Links: |
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| Themen: |
Immunotherapy |
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| Anmerkungen: |
Date Revised 10.08.2022 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.jtocrr.2022.100373 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM344614174 |
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| 100 | 1 | |a Kanemura, Hiroaki |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC |
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| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2022 The Authors. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a Clinical trial registration: UMIN000041056 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Neoantigen | |
| 650 | 4 | |a Small cell lung cancer | |
| 650 | 4 | |a Tumor mutation burden | |
| 650 | 4 | |a Tumor-infiltrating lymphocyte | |
| 700 | 1 | |a Hayashi, Hidetoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Tomida, Shuta |e verfasserin |4 aut | |
| 700 | 1 | |a Tanizaki, Junko |e verfasserin |4 aut | |
| 700 | 1 | |a Suzuki, Shinichiro |e verfasserin |4 aut | |
| 700 | 1 | |a Kawanaka, Yusuke |e verfasserin |4 aut | |
| 700 | 1 | |a Tsuya, Asuka |e verfasserin |4 aut | |
| 700 | 1 | |a Fukuda, Yasushi |e verfasserin |4 aut | |
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| 700 | 1 | |a Takahama, Takayuki |e verfasserin |4 aut | |
| 700 | 1 | |a Imai, Ryosuke |e verfasserin |4 aut | |
| 700 | 1 | |a Haratani, Koji |e verfasserin |4 aut | |
| 700 | 1 | |a Chiba, Yasutaka |e verfasserin |4 aut | |
| 700 | 1 | |a Otani, Tomoyuki |e verfasserin |4 aut | |
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| 700 | 1 | |a Nishio, Kazuto |e verfasserin |4 aut | |
| 700 | 1 | |a Nakagawa, Kazuhiko |e verfasserin |4 aut | |
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