Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions.

Anders Tøndell,Yashwanth Subbannayya,Markus Haug,Sissel Gyrid Freim Wahl,Magne Børset,Arnar Flatberg,Sveinung Sørhaug

doi:10.3390/cancers13081788

Anders Tøndell, Yashwanth Subbannayya + Show 5 more

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https://doi.org/10.3390/cancers13081788

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Abstract

Simple SummaryLung cancer is the leading cause of cancer-related death worldwide, accounting for nearly one-fifth of all cancer-related deaths. Immunotherapy with immune checkpoint inhibitors has become one of the most promising approaches in the treatment of advanced lung cancer, although beneficial responses are seen only in a proportion of patients. To improve immunotherapy treatment responses in lung cancer, we need to identify which immunosuppression mechanisms are activated in the tumor microenvironment. In this study, we investigated gene expression profiles in intra-tumoral immune cells in lung cancer, focusing on tumor-associated macrophages, and interactions with CD4+ and CD8+ T cells. Our data highlight two newly described immunosuppressive pathways, which may represent novel innate immune checkpoints dampening the anti-tumor T cell immune response in lung cancer. Our results substantiate the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.Non-small cell lung carcinoma (NSCLC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths. Immunotherapy with immune checkpoint inhibitors shows beneficial responses, but only in a proportion of patients. To improve immunotherapy in NSCLC, we need to map the immune checkpoints that contribute immunosuppression in NSCLC-associated immune cells and to identify novel pathways that regulate immunosuppression. Here, we investigated the gene expression profiles of intra-tumoral immune cells isolated from NSCLC patients and compared them to the expression profiles of their counterparts in adjacent healthy tissue. Transcriptome analysis was performed on macrophages, CD4+ and CD8+ T cells. The data was subjected to Gene Ontology (GO) term enrichment and weighted correlation network analysis in order to identify mediators of immunosuppression in the tumor microenvironment in NSCLC. Immune cells from NSCLC revealed a consistent differential expression of genes involved in interactions between myeloid cells and lymphocytes. We further identified several immunosuppressive molecules and pathways that may be activated in tumor-associated macrophages in NSCLC. Importantly, we report novel data on immune cell expression of the newly described CD200/CD200R1 pathway, and the leukocyte immunoglobulin-like receptors (LILRs), which may represent novel innate immune checkpoints, dampening the anti-tumor T cell immune response in NSCLC. Our study substantiates the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.

Highlights

Lung cancer is the most commonly diagnosed cancer, and the leading cause of cancerrelated death [1], accounting for an estimated 1.8 million deaths worldwide in 2018, which is nearly one-fifth of all cancer-related deaths [2]
Principal component analysis segregated the transcriptomic profiles of Tumor-associated macrophages (TAMs) and macrophages isolated from adjacent healthy tissue, which indicates systematic differences between tumor and non-tumor macrophages that are not overshadowed by the variations between donors (Figure 1A)
A list of genes mentioned in this manuscript is provided in Table 2, showing the ratio between gene expression in cells from a tumor and in cells from healthy tissue for macrophages, CD4+ and CD8+ T cells

Summary

Introduction

Lung cancer is the most commonly diagnosed cancer, and the leading cause of cancerrelated death [1], accounting for an estimated 1.8 million deaths worldwide in 2018, which is nearly one-fifth of all cancer-related deaths [2]. Non-small cell lung carcinoma (NSCLC) accounts for about 85% of all lung cancers and has a predicted five-year survival rate of 23% [2] One reason for this low survival rate is that the majority of patients are diagnosed with advanced disease. Clinical studies show beneficial long-term responses only in a proportion of patients [5,6] and effective immunotherapy options are still lacking for the majority of patients with advanced NSCLC. This may be caused by innate or acquired resistance to immune checkpoint inhibitors [7], e.g., due to a compensatory upregulation of other checkpoint receptors [8]. Immunotherapies attacking several novel targets are currently in clinical trials or are under development [11]

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