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

Abstract

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.

Targeting tumor-associated macrophage: an adjuvant strategy for lung cancer therapy

“…TAMs or TAM-related molecules, such as IL37 receptor (IL37R), macrophage receptors with collagenous structure (MARCO), CD200, and c-Maf, inhibit TAM proliferation and cytokine production, and block the activation of cytotoxic T cells and natural killer cells. Notably, targeting these molecules with an antibody or knockout of these molecules may repolarize TAMs, thereby recovering the anti-tumoral ability of T cells and natural killer cells, as well as the activities of downmodulated regulatory T cells (24)(25)(26).…”

Emerging Immune Checkpoint Molecules on Cancer Cells: CD24 and CD200

“…CD200 is overexpressed in 29.7% of non-small-cell lung cancer (NSCLC) patients and 33.3% of patients with lung large-cell neuroendocrine carcinoma (LCNEC), exhibiting a moderate correlation with PD-L1 expression [111]. Tondell et al demonstrated that CD200 expression was higher in intratumoral CD4 + T cells from patients with NSCLC than that in CD4 + T cells from normal lungs, and further elucidated the relationship between elevated CD200 expression in lung cancer tissue and reduced survival [112]. Compared with the substantially low CD200 expression level observed in healthy controls, high CD200 expression was observed in peritumoral stroma from patients with HCC [113].…”

Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy

“… 4 , 5 , 6 CD200 acts via its receptor (CD200R) to activate Dok-1 and -2, RasGAP, and SHIP, 7 suppressing the activity of CD200R + cells including T and natural killer cells. 8 Tumors from a variety of solid 9 , 10 , 11 , 12 , 13 and hematological malignancies, 14 , 15 including MM, 6 , 10 , 16 , 17 , 18 , 19 , 20 , 21 co-opt the CD200-CD200R pathway to limit antitumoral immune responses. Moreover, CD200 is expressed on regulatory T, 22 B, 23 and dendritic 24 cells and is a marker for cancer stem cells in both hematological and solid cancers in which it functions as a tolerogenic factor.…”