Abstract
Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). Results: NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 127-139 |
| Number of pages | 13 |
| Journal | Journal of Thoracic Oncology |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
Keywords
- B cell
- Cytotoxic T cell
- Neoadjuvant chemotherapy
- Non–small cell lung cancer
- Tissue resident memory T cell
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
MD Anderson CCSG core facilities
- Bioinformatics Shared Resource
- Tissue Biospecimen and Pathology Resource
- Research Histology Core Lab
- Clinical Trials Office
- Flow Cytometry and Cellular Imaging Facility
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In: Journal of Thoracic Oncology, Vol. 16, No. 1, 01.2021, p. 127-139.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC
AU - Gaudreau, Pierre Olivier
AU - Negrao, Marcelo V.
AU - Mitchell, Kyle G.
AU - Reuben, Alexandre
AU - Corsini, Erin M.
AU - Li, Jun
AU - Karpinets, Tatiana V.
AU - Wang, Qi
AU - Diao, Lixia
AU - Wang, Jing
AU - Federico, Lorenzo
AU - Parra-Cuentas, Edwin R.
AU - Khairullah, Roohussaba
AU - Behrens, Carmen
AU - Correa, Arlene M.
AU - Gomez, Daniel
AU - Little, Latasha
AU - Gumbs, Curtis
AU - Kadara, Humam N.
AU - Fujimoto, Junya
AU - McGrail, Daniel J.
AU - Vaporciyan, Ara A.
AU - Swisher, Stephen G.
AU - Walsh, Garrett
AU - Antonoff, Mara B.
AU - Weissferdt, Annikka
AU - Tran, Hai
AU - Roarty, Emily
AU - Haymaker, Cara
AU - Bernatchez, Chantale
AU - Zhang, Jianhua
AU - Futreal, P. Andrew
AU - Wistuba, Ignacio I.
AU - Cascone, Tina
AU - Heymach, John V.
AU - Sepesi, Boris
AU - Zhang, Jianjun
AU - Gibbons, Don L.
N1 - Funding Information: This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the Gil and Dody Weaver Foundation and Bill and Katie Weaver Charitable Trust, the MD Anderson Cancer Center support grant P30 CA01667 , MD Anderson Physician Scientist Program, and the Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award grant (The Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award Grant: RP160668). Dr. Gaudreau was supported by the Fonds de Recherche Québec–Santé’s (FRQS) Resident Physician Health Research Career Training Program (32667). The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. This work used the Tissue Biospecimen and Pathology Resource and Research Histopathology Facility at MD Anderson. This project was in part supported by the Translational Molecular Pathology-Immunoprofiling Laboratory (TMP-IL) at the Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center . The authors appreciate the assistance of Elliana Young with the Department of Institutional Analytics and Informatics at MD Anderson. The authors thank all the dedication of the research nurses Mary Ann Gianan and Craig DeGraaf, consent team May Celestino, blood team Patrice Lawson, Heather Napoleon, Mayra Vasquez, and Eric Prado, and all thoracic or nurses and anesthesiologists at MD Anderson Cancer Center, without whom this work could not have been completed. Dr. Gaudreau, Dr. Negrao, Dr. Mitchell, Dr. Reuben, Dr. Corsini, Dr. Li, Dr. Karpinets, Dr. Federico, Dr. Parra-Cuentas, Ms. Khairullah, Dr. Gomez, Ms. Little, Mr. Gumbs, Dr. Kadara, Dr. Fujimoto, Dr. Tran, Dr. Haymaker, Dr. Bernatchez, Dr. Jinhua Zhang, Dr. Cascone, Dr. Futreal, Dr. Wistuba, Dr. Heymach, Dr. Sepesi, Dr. Jianjun Zhang, and Dr. Gibbons conceived and designed the experiments. All authors contributed to data collection. Dr. Gaudreau, Dr. Negrao, Dr. Mitchell, Dr. Reuben, Dr. Corsini, Li, Dr. Karpinets, Dr. Wang, Dr. Diao, Dr. Wang, Dr. Federico, Dr. Parra-Cuentas, Ms. Khairullah, Ms. Little, Mr. Gumbs, Dr. Kadara, Dr. Fujimoto, Dr. Tran, Dr. Haymaker, Dr. Bernatchez, Dr. Jinhua Zhang, Dr. Cascone, Dr. Futreal, Dr. Wistuba, Dr. Heymach, Dr. Sepesi, Dr. Jianjun Zhang, and Dr. Gibbons contributed to data analysis. Dr. Gaudreau wrote the first draft of the manuscript. Drs. Gaudreau, Negrao, Mitchell, Reuben, Corsini, Li, Karpinets, Wang, Federico, Parra-Cuentas, Haymaker, Bernatchez, Cascone, Wistuba, Heymach, Sepesi, Jianjun Zhang, and Gibbons contributed to the writing of the manuscript. All authors agree with manuscript results and conclusions. Drs. Gaudreau, Negrao, Jianjun Zhang, and Gibbons jointly developed the structure and arguments for the article. Drs. Gaudreau, Negrao, Jianjun Zhang, and Gibbons made critical revisions and approved the final version. All authors reviewed and approved the final manuscript. Funding Information: Disclosure: Dr. Gibbons has received research funding from AstraZeneca, Astellas, Janssen, Ribon Therapeutics, and Takeda Pharmaceutical, and has participated in advisory boards for AstraZeneca and Sanofi. Dr. Swisher has participated in advisory committees for Ethicon and Peter MacCallum Cancer Center. Dr. Heymach has received research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum; has participated in advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Eli Lilly, Novartis, Spectrum, EMD Serono, and Synta; and received royalties or licensing fees from Spectrum. Dr. Cascone reports speaker's fees from Society for Immunotherapy of Cancer (SITC) and Bristol-Myers Squibb, consulting fees from MedImmune/AstraZeneca and Bristol-Myers Squibb, and advisory role fees from EMD Serono and Bristol-Myers Squibb and clinical research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/AstraZeneca, EMD Serono, and Bristol-Myers Squibb. Dr. Zhang served on the advisory board for AstraZeneca and Geneplus and has received speaker's fees from Bristol-Myers Squibb, Geneplus, OrigMed, and Innovent and grant from Merck outside of the submitted work. The remaining authors declare no conflict of interest.This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the Gil and Dody Weaver Foundation and Bill and Katie Weaver Charitable Trust, the MD Anderson Cancer Center support grant P30 CA01667, MD Anderson Physician Scientist Program, and the Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award grant (The Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award Grant: RP160668). Dr. Gaudreau was supported by the Fonds de Recherche Qu?bec?Sant??s (FRQS) Resident Physician Health Research Career Training Program (32667). The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. This work used the Tissue Biospecimen and Pathology Resource and Research Histopathology Facility at MD Anderson. This project was in part supported by the Translational Molecular Pathology-Immunoprofiling Laboratory (TMP-IL) at the Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center. The authors appreciate the assistance of Elliana Young with the Department of Institutional Analytics and Informatics at MD Anderson. The authors thank all the dedication of the research nurses Mary Ann Gianan and Craig DeGraaf, consent team May Celestino, blood team Patrice Lawson, Heather Napoleon, Mayra Vasquez, and Eric Prado, and all thoracic or nurses and anesthesiologists at MD Anderson Cancer Center, without whom this work could not have been completed. Dr. Gaudreau, Dr. Negrao, Dr. Mitchell, Dr. Reuben, Dr. Corsini, Dr. Li, Dr. Karpinets, Dr. Federico, Dr. Parra-Cuentas, Ms. Khairullah, Dr. Gomez, Ms. Little, Mr. Gumbs, Dr. Kadara, Dr. Fujimoto, Dr. Tran, Dr. Haymaker, Dr. Bernatchez, Dr. Jinhua Zhang, Dr. Cascone, Dr. Futreal, Dr. Wistuba, Dr. Heymach, Dr. Sepesi, Dr. Jianjun Zhang, and Dr. Gibbons conceived and designed the experiments. All authors contributed to data collection. Dr. Gaudreau, Dr. Negrao, Dr. Mitchell, Dr. Reuben, Dr. Corsini, Li, Dr. Karpinets, Dr. Wang, Dr. Diao, Dr. Wang, Dr. Federico, Dr. Parra-Cuentas, Ms. Khairullah, Ms. Little, Mr. Gumbs, Dr. Kadara, Dr. Fujimoto, Dr. Tran, Dr. Haymaker, Dr. Bernatchez, Dr. Jinhua Zhang, Dr. Cascone, Dr. Futreal, Dr. Wistuba, Dr. Heymach, Dr. Sepesi, Dr. Jianjun Zhang, and Dr. Gibbons contributed to data analysis. Dr. Gaudreau wrote the first draft of the manuscript. Drs. Gaudreau, Negrao, Mitchell, Reuben, Corsini, Li, Karpinets, Wang, Federico, Parra-Cuentas, Haymaker, Bernatchez, Cascone, Wistuba, Heymach, Sepesi, Jianjun Zhang, and Gibbons contributed to the writing of the manuscript. All authors agree with manuscript results and conclusions. Drs. Gaudreau, Negrao, Jianjun Zhang, and Gibbons jointly developed the structure and arguments for the article. Drs. Gaudreau, Negrao, Jianjun Zhang, and Gibbons made critical revisions and approved the final version. All authors reviewed and approved the final manuscript. Funding Information: Disclosure: Dr. Gibbons has received research funding from AstraZeneca , Astellas , Janssen , Ribon Therapeutics, and Takeda Pharmaceutical , and has participated in advisory boards for AstraZeneca and Sanofi. Dr. Swisher has participated in advisory committees for Ethicon and Peter MacCallum Cancer Center. Dr. Heymach has received research support from AstraZeneca , Bayer , GlaxoSmithKline , and Spectrum ; has participated in advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Eli Lilly, Novartis, Spectrum, EMD Serono, and Synta; and received royalties or licensing fees from Spectrum. Dr. Cascone reports speaker’s fees from Society for Immunotherapy of Cancer (SITC) and Bristol-Myers Squibb, consulting fees from MedImmune/AstraZeneca and Bristol-Myers Squibb, and advisory role fees from EMD Serono and Bristol-Myers Squibb and clinical research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/AstraZeneca, EMD Serono, and Bristol-Myers Squibb. Dr. Zhang served on the advisory board for AstraZeneca and Geneplus and has received speaker’s fees from Bristol-Myers Squibb, Geneplus, OrigMed, and Innovent and grant from Merck outside of the submitted work. The remaining authors declare no conflict of interest. Publisher Copyright: © 2020 International Association for the Study of Lung Cancer
PY - 2021/1
Y1 - 2021/1
N2 - Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). Results: NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
AB - Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). Results: NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
KW - B cell
KW - Cytotoxic T cell
KW - Neoadjuvant chemotherapy
KW - Non–small cell lung cancer
KW - Tissue resident memory T cell
UR - http://www.scopus.com/inward/record.url?scp=85096854484&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096854484&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2020.09.027
DO - 10.1016/j.jtho.2020.09.027
M3 - Article
C2 - 33096269
AN - SCOPUS:85096854484
SN - 1556-0864
VL - 16
SP - 127
EP - 139
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 1
ER -