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Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer
The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patie...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279502/ https://www.ncbi.nlm.nih.gov/pubmed/35831288 http://dx.doi.org/10.1038/s41467-022-31769-4 |
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author | Lau, Denise Khare, Sonal Stein, Michelle M. Jain, Prerna Gao, Yinjie BenTaieb, Aicha Rand, Tim A. Salahudeen, Ameen A. Khan, Aly A. |
author_facet | Lau, Denise Khare, Sonal Stein, Michelle M. Jain, Prerna Gao, Yinjie BenTaieb, Aicha Rand, Tim A. Salahudeen, Ameen A. Khan, Aly A. |
author_sort | Lau, Denise |
collection | PubMed |
description | The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4(+) T cells that express a canonical cytotoxic gene program and NSCLC cells with elevated HLA-II expression. We postulate cytotoxic CD4(+) T cells mediate anti-tumor activity via HLA-II on tumor cells and augment HLA-I-dependent cytotoxic CD8(+) T cell interactions to drive ICB response in NSCLC. We show that integrating tumor extrinsic cytotoxic gene expression with tumor mutational burden is associated with longer time to progression in a real-world cohort of 123 NSCLC patients treated with ICB regimens, including those with HLA-LOH. |
format | Online Article Text |
id | pubmed-9279502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92795022022-07-15 Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer Lau, Denise Khare, Sonal Stein, Michelle M. Jain, Prerna Gao, Yinjie BenTaieb, Aicha Rand, Tim A. Salahudeen, Ameen A. Khan, Aly A. Nat Commun Article The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4(+) T cells that express a canonical cytotoxic gene program and NSCLC cells with elevated HLA-II expression. We postulate cytotoxic CD4(+) T cells mediate anti-tumor activity via HLA-II on tumor cells and augment HLA-I-dependent cytotoxic CD8(+) T cell interactions to drive ICB response in NSCLC. We show that integrating tumor extrinsic cytotoxic gene expression with tumor mutational burden is associated with longer time to progression in a real-world cohort of 123 NSCLC patients treated with ICB regimens, including those with HLA-LOH. Nature Publishing Group UK 2022-07-13 /pmc/articles/PMC9279502/ /pubmed/35831288 http://dx.doi.org/10.1038/s41467-022-31769-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lau, Denise Khare, Sonal Stein, Michelle M. Jain, Prerna Gao, Yinjie BenTaieb, Aicha Rand, Tim A. Salahudeen, Ameen A. Khan, Aly A. Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
title | Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
title_full | Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
title_fullStr | Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
title_full_unstemmed | Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
title_short | Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
title_sort | integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279502/ https://www.ncbi.nlm.nih.gov/pubmed/35831288 http://dx.doi.org/10.1038/s41467-022-31769-4 |
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