Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC

Pierre-Olivier Gaudreau; Marcelo V Negrao; Kyle G Mitchell; Alexandre Reuben; Erin M Corsini; Jun Li; Tatiana V Karpinets; Qi Wang; Lixia Diao; Jing Wang; Lorenzo Federico; Edwin R Parra-Cuentas; Roohussaba Khairullah; Carmen Behrens; Arlene M Correa; Daniel Gomez; Latasha Little; Curtis Gumbs; Humam N Kadara; Junya Fujimoto; Daniel J McGrail; Ara A Vaporciyan; Stephen G Swisher; Garrett Walsh; Mara B Antonoff; Annikka Weissferdt; Hai Tran; Emily Roarty; Cara Haymaker; Chantale Bernatchez; Jianhua Zhang; P Andrew Futreal; Ignacio I Wistuba; Tina Cascone; John V Heymach; Boris Sepesi; Jianjun Zhang; Don L Gibbons

doi:10.1016/j.jtho.2020.09.027

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC

J Thorac Oncol. 2021 Jan;16(1):127-139. doi: 10.1016/j.jtho.2020.09.027. Epub 2020 Oct 21.

Authors

Pierre-Olivier Gaudreau¹, Marcelo V Negrao², Kyle G Mitchell³, Alexandre Reuben², Erin M Corsini³, Jun Li⁴, Tatiana V Karpinets⁴, Qi Wang⁵, Lixia Diao⁵, Jing Wang⁵, Lorenzo Federico⁶, Edwin R Parra-Cuentas⁷, Roohussaba Khairullah², Carmen Behrens², Arlene M Correa³, Daniel Gomez⁸, Latasha Little⁴, Curtis Gumbs⁴, Humam N Kadara⁷, Junya Fujimoto⁷, Daniel J McGrail⁹, Ara A Vaporciyan³, Stephen G Swisher³, Garrett Walsh³, Mara B Antonoff³, Annikka Weissferdt¹⁰, Hai Tran², Emily Roarty², Cara Haymaker⁷, Chantale Bernatchez¹¹, Jianhua Zhang⁴, P Andrew Futreal⁴, Ignacio I Wistuba⁷, Tina Cascone², John V Heymach², Boris Sepesi³, Jianjun Zhang¹², Don L Gibbons¹³

Affiliations

¹ Department of Oncology, Queens' University and the Canadian Cancer Trials Group, Kingston, Ontario, Canada.
² Department of Thoracic and Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
³ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁴ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁶ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁷ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁸ Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
⁹ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁰ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
¹¹ Biologics Development Department, The University of Texas MD Anderson Cancer Center, Houston, Texas.
¹² Department of Thoracic and Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: [email protected].
¹³ Department of Oncology, Queens' University and the Canadian Cancer Trials Group, Kingston, Ontario, Canada; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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.

Keywords: B cell; Cytotoxic T cell; Neoadjuvant chemotherapy; Non–small cell lung cancer; Tissue resident memory T cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes
CD8-Positive T-Lymphocytes
Humans
Immunologic Memory
Lung Neoplasms* / drug therapy
Neoadjuvant Therapy*
Tumor Microenvironment

Abstract

Publication types

MeSH terms

Grants and funding