Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer
Year: 2022
Type: article
Study design: Observational Study
Abstract: Background Tumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored. Methods We used multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8+ cytotoxic T cells, CD4+ helper T cells and CD20+ B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI. The analysis of full-face tumor biopsies including numerous fields of view allowed a detailed spatial analysis and assessment of tumor immune heterogeneity using a multiparametric quadratic entropy metric (Rao’s Q Index (RQI)). Results TILs were preferentially located in the stromal tissue areas surrounding tumor-cell nests and CD8+ T cells were the most abundant subset. Higher density of stromal CD8+ cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases. The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed measuring the T cell receptor-burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort. Conclusion Baseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC.
Institutions: Yale Cancer Center, Yale University, Harvard University, Dana-Farber Cancer Institute, Massachusetts General Hospital, Case Western Reserve University, Louis Stokes Cleveland VA Medical Center, UC Davis Comprehensive Cancer Center, University of California, Davis, NYU Langone Health, New York University, Memorial Sloan Kettering Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
Funders: American Cancer Society, U.S. Department of Veterans Affairs, Mark Foundation For Cancer Research, National Institutes of Health, Stand Up To Cancer, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1044130170, RadxTools for assessing tumor treatment response on imaging, G1266336578, G1478154455, G1596146291, G1780856649, Lung cancer in East Africa and the relationship to HIV-1 infection: epidemiology, molecular characterization and imaging, A Study to Validate and Improve an Automated Image Analysis Algorithm to Detect Tuberculosis in Sputum Smear Slides, G2228475719, G338730684, G3564444776, G388216630, HistoTools: A suite of digital pathology tools for quality control, annotation and dataset identification, G5690715282, G6815883710, G776903742, G80075099, G86714149, G9000004526, G9000291772, Cancer Center Support Grant, Quantitative and Spatially-Resolved Analysis of the Tumor Immune Contexture for Optimal Diagnosis and Treatment of Lung Cancer, Novel Radiomics for Predicting Response to Immunotherapy for Lung Cancer, Cancer Center Support Grant P30, Yale Clinical and Translational Science Award
OpenAlex ID: W4281706766