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Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer.

ABSTRACT: 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.

SUBMITTER: Lau D

PROVIDER: S-EPMC9279502 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer.

Lau Denise D Khare Sonal S Stein Michelle M MM Jain Prerna P Gao Yinjie Y BenTaieb Aicha A Rand Tim A TA Salahudeen Ameen A AA Khan Aly A AA

Nature communications 20220713 1

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 expande ...[more]

PMID: 35831288

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Project description:Historically, non-small-cell lung cancer (NSCLC) has been regarded as a nonimmunogenic tumor; however, recent studies have shown that NSCLCs are among the most responsive cancers to monoclonal antibody immune checkpoint inhibitors (ICIs). ICIs have dramatically improved clinical outcomes for a subset of patients (∼20%) with locally advanced and metastatic NSCLC, and they have also demonstrated promise as neoadjuvant therapy for early-stage resectable disease. Nevertheless, the majority of patients with NSCLC are refractory to ICIs for reasons that are poorly understood. Thus, major questions are: how do we initially identify the patients most likely to derive significant clinical benefit from these therapies; how can we increase the number of patients benefiting; what are the mechanisms of primary and acquired resistance to immune-based therapies; are there additional immune checkpoints besides PD-1/PD-L1 and CTLA-4 that can be targeted to provide greater clinical benefit to patients; and how do we best combine ICI therapy with surgery, radiotherapy, chemotherapy, and targeted therapy? To answer these questions, we need to deploy the latest technologies to study tumors and their microenvironment and how they interact with components of the innate and adaptive immune systems. There is also a need for new preclinical model systems to investigate the molecular mechanisms of resistance to treatment and identify novel therapeutic targets. Recent advances in technology are beginning to shed new light on the immune landscape of NSCLC that may uncover biomarkers of response and maximize the clinical benefit of immune-based therapies. Identification of the mechanisms of resistance should lead to the identification of novel targets and the generation of new therapeutic strategies that improve outcomes for a greater number of patients. In the sections below, we discuss the results of studies examining the immune microenvironment in NSCLC, summarize the clinical experience with immunotherapy for NSCLC, and review candidate biomarkers of response to these agents in NSCLC.

Project description:Simple Summary Monoclonal antibodies targeting the programmed death 1 (PD-1) receptor and its ligand (PD-L1) have demonstrated improved clinical response and survival in non-small cell lung cancer (NSCLC). Although extrinsic immunologic factors play important roles in the regulation of PD-L1 and PD-1, tumor intrinsic factors, including genetic alterations, epigenetic alterations, oncogenic and tumor suppressor signals, and transcription factors also play important roles in PD-L1 expression. There is an urgent need to investigate the intrinsic transcriptional profiles affecting the clinical response to PD-1 inhibitors in patients with non-small cell lung cancer. In our study, PD-1 inhibitor-associated intrinsic gene patterns were very different between lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, the intrinsic gene signature was a very good predictive or prognostic biomarker. Our findings prove for the first time that an intrinsic gene signature is well predictive of responsiveness to PD-1 inhibitors in lung adenocarcinoma. Abstract Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) = 0.957 and mean accuracy = 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (p = 0.034). When we performed a pathway enrichment analysis, the cell cycle and cellular senescence pathways were related to the upregulation of intrinsic genes in LUAD. The intrinsic signature of LUAD also showed a positive correlation with other immune checkpoint targets, including CD274, LAG3, and PDCD1LG2 (Spearman correlation coefficient > 0.25). PD-1 inhibitor-related intrinsic gene patterns differed significantly between LUAD and LUSC and may be a particularly useful biomarker in LUAD.

Dataset Information

Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer.

Publications

Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer.

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