Inverse relationship found between anti-inflammatory macrophages and NK cells/T cells in lung cancer

The tumor microenvironment in lung cancer, particularly the interactions involving myeloid cells like macrophages, plays a crucial role in tumor progression.

In a recent study published in Nature Communications, researchers combined single-cell ribonucleic acid sequencing (scRNAseq) and spatial transcriptomics to study cellular organization and interactions within the tumor microenvironment in patients with squamous-cell carcinoma and adenocarcinoma.

​​​​​​​​​​​​​Study: Single-cell and spatial transcriptomics analysis of non-small cell lung cancer. Image Credit: mi_viri/​​​​​​​​​​​​​Study: Single-cell and spatial transcriptomics analysis of non-small cell lung cancer. Image Credit: mi_viri/


Lung cancer is one of the most prevalent forms of cancer and is the leading cause of cancer-related mortality worldwide. The most common form of lung cancer is non-small-cell lung cancer (NSCLC), making up approximately 85% of the cases, while small-cell lung cancer (SCLC) constitutes the remaining cases of lung cancer.

Adenocarcinoma is the histological subtype of NSCLC that occurs more frequently than the squamous-cell carcinoma subtype.

The tumor microenvironment in lung cancer is critical to the progression or suppression of the tumor. Myeloid cells, such as macrophages, are central in promoting tumor growth.

Studies have shown that tumor-associated macrophages have dual roles in cancer. On one hand, they promote tumor growth by facilitating tissue remodeling and angiogenesis and suppressing immune responses. On the other hand, they can suppress tumors by participating in cytotoxic activity against tumor cells and aiding inflammation.

About the Study

In the present study, the researchers aimed to understand the complex interplay between macrophages and cancer cells in the tumor microenvironment to determine the interactions contributing to tumor progression, which can be targeted for more effective treatment methods.

Although numerous studies have used single-cell sequencing methods to examine the transcriptional changes that occur within the NSCLC microenvironment, the lack of adequate data and the absence of sequences from non-tumor tissue from matched patients has presented challenges in understanding the biological heterogeneity in the tumor tissue and the surrounding non-tumor tissue.

Furthermore, most studies grouped squamous-cell carcinomas and adenocarcinomas despite the significant differences in pathology and molecular characteristics.

In addition, while scRNAseq can provide high-resolution data on the types and states of cells, it cannot provide spatial distribution information or determine the interactions between cells, receptors, or ligands.

The use of spatial transcriptomics along with scRNAseq allowed the researchers to examine how cellular organizations within the tumor microenvironment differed from those within surrounding non-tumor tissue.

They also investigated the macrophage populations within the tumor microenvironment and the molecular changes that occur within them.

Resections of lung tissue were obtained from 25 patients who were treatment-naive and had either squamous-cell carcinoma, adenocarcinoma, or an undetermined form of lung cancer.

Healthy lung tissue samples from deceased donors were used as non-tumorigenic lung tissue. Tumor cells, CD45+ immune cells, and non-immune cell populations were isolated from these tissues for scRNAseq using fluorescence-activated cell sorting.

Additionally, the abundance of various cell types was contrasted between different sample types. Significant pairs of ligands, receptors, and corresponding cell types were statistically analyzed to identify differential interactions between cells in the tumor microenvironment.

Analyses of differential expression, copy number, immunohistochemistry, spatial cell typing, and colocalization of ligands and receptors were also used to understand the tumor microenvironment.

Major Findings

The study reported that anti-inflammatory macrophages within the tumor microenvironment displayed an inverse relationship with T cells, natural killer cells, and lower natural killer cell cytotoxicity. The immunosuppressive phenotype further prevented natural killer cells from infiltrating the tumor microenvironment.

Furthermore, although the composition of cell types was similar in squamous-cell carcinomas and adenocarcinomas, numerous immune checkpoint inhibitors were differentially co-expressed in the two subtypes of NSCLC.

Adenocarcinomas showed increased expression of TIM3 and TIGIT, while the putative immune checkpoint inhibitor CD96-NECTIN1 was found to be expressed in squamous-cell carcinomas. Most clinical trials have targeted TIGIT, but not many have focused on CD96 or TIM3.

The anti-inflammatory macrophages were also transcriptionally reprogrammed to upregulate gene expression in lipid metabolism and cholesterol trafficking.

The immunosuppressive phenotype was exacerbated by the subsequent downregulation of chemokines, cytokines, and other co-stimulatory molecules essential for recruiting CD8+ T cells.

The transcriptional signatures in the tumor macrophages were very similar to those found in fetal lungs, suggesting that within the tumor microenvironment in NSCLC, macrophages undergo oncofetal reprogramming, increasing the expression of genes involved in iron release.


To summarize, the findings reported numerous molecular changes and transcriptional reprogramming within tumor-associated macrophage populations, contributing to immunosuppression and tumor growth promotion.

This new understanding of the tumor microenvironment presents opportunities and targets for developing more effective therapies.

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