Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.

Abstract

Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). We confirmed LCAMhi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAMhi lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.

• Authors: Andrew M Leader, John A Grout, Barbara B Maier, Barzin Y Nabet, Matthew D Park, Alexandra Tabachnikova, Christie Chang, Laura Walker, Alona Lansky, Jessica Le Berichel, Leanna Troncoso, Nausicaa Malissen, Melanie Davila, Jerome C Martin, Giuliana Magri, Kevin Tuballes, Zhen Zhao, Francesca Petralia, Robert Samstein, Natalie Roy D'Amore, Gavin Thurston, Alice O Kamphorst, Andrea Wolf, Raja Flores, Pei Wang, Sören Müller, Ira Mellman, Mary Beth Beasley, Hélène Salmon, Adeeb H Rahman, Thomas U Marron, Ephraim Kenigsberg, Miriam Merad
• Journal: Cancer cell (Cancer Cell) Vol. 39 Issue 12 Pg. 1594-1609.e12 (12 13 2021) ISSN: 1878-3686 [Electronic] United States
• PMID: 34767762 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Topics

• Carcinoma, Non-Small-Cell Lung (immunology)
• Humans
• Immunotherapy (methods)
• Lung Neoplasms (immunology)
• Single-Cell Analysis (methods)