Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma

Author:

Fan Fanfan123ORCID,Gao Jian14ORCID,Zhao Yue123ORCID,Wang Jun5ORCID,Meng Lu6ORCID,Ma Jiaqiang6ORCID,Li Teng6ORCID,Han Han123ORCID,Lai Jinglei123ORCID,Gao Zhendong123ORCID,Li Xiongfei123ORCID,Guo Ran123ORCID,Cao Zhiwei5ORCID,Zhang Yang123ORCID,Zhang Xiaoming6ORCID,Chen Haiquan123ORCID

Affiliation:

1. 1Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.

2. 2Institute of Thoracic Oncology, Fudan University, Shanghai, China.

3. 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

4. 4International Human Phenome Institutes, Shanghai, China.

5. 5School of Life Sciences, Fudan University, Shanghai, China.

6. 6The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.

Abstract

Abstract Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) of patient LUAD samples to comprehensively characterize LUAD-infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ CTL, a specific subcluster of preexhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential cross-talk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD. Significance: Comprehensive characterization of mast cells in lung adenocarcinoma elucidates their heterogeneity and identifies interplay between mast cells and CCR2+ T cells that is associated with a favorable prognosis.

Funder

National Natural Science Foundation of China

Science and Technology Innovation Plan Of Shanghai Science and Technology Commission

National Key Research and Development Program of China

Cooperation Project of Conquering Major Diseases in Xuhui Distrit

Shanghai Sailing Program

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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