Phenotypic and Histological Distribution Analysis Identify Mast Cell Heterogeneity in Non-Small Cell Lung Cancer

Abstract

Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). However, MCs have been only barely characterized in studies focusing on global immune infiltrate phenotyping. Consequently, their role in cancer is still poorly understood. Furthermore, their prognosis value is confusing since MCs have been associated with good and bad (or both) prognosis depending on the cancer type. In this pilot study performed on a surgical cohort of 48 patients with Non-Small Cell Lung Cancer (NSCLC), we characterized MC population within the TME and in matching non-lesional lung areas, by multicolor flow cytometry and confocal microscopy. Our results showed that tumor-associated MCs (TAMCs) harbor a distinct phenotype as compared with MCs present in non-lesional counterpart of the lung. Moreover, we found two TAMCs subsets based on the expression of CD103 (also named alphaE integrin). CD103+ TAMCs appeared more mature, more prone to interact with CD4+ T cells, and located closer to cancer cells than their CD103− counterpart. In spite of these characteristics, we did not observe a prognosis advantage of a high frequency of CD103+ TAMCs, while a high frequency of total TAMC correlated with better overall survival and progression free survival. Together, this study reveals that TAMCs constitute a heterogeneous population and indicates that MC subsets should be considered for patients’ stratification and management in future research.

Comprehensive analysis of a novel signature incorporating lipid metabolism and immune-related genes for assessing prognosis and immune landscape in lung adenocarcinoma

“…This, in turn, effectively activated T cells. The study also indicated that lung cancer patients with high mast cell infiltration in the tumor microenvironment exhibited better overall and disease-free survival ( 69 ). In addition, it has been reported that MHC protein is one of the key molecules in presenting antigens and activating T lymphocytes for anti-tumor immunity ( 70 ).…”

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy

“…The number of infiltrating MCs correlated positively with poor cancer prognosis 78 , 79 . Recently, Leveque et al have demonstrated that tumor-associated mast cells (TAMCs), a heterogeneous population, harbor a distinct phenotype compared to MCs present in the non-lesional homologue of lung cancer 80 . It is further noted that the TAMCs subset expressing alpha E integrin, namely CD103+ TAMCs, appeared more actively to interact with CD4+ T cells and located closer to tumor cells than their CD103- counterparts.…”

“…It is further noted that the TAMCs subset expressing alpha E integrin, namely CD103+ TAMCs, appeared more actively to interact with CD4+ T cells and located closer to tumor cells than their CD103- counterparts. Recruitment of TAMCs was mediated by chemotactic agents released by TME, such as VEGF, CXC chemokine ligand (CXCL)12, PGE2, and platelet-derived growth factor (PDGF) 80 , 81 . Activated TAMCs could express CCL5 and IL-33 to further recruit MCs into tumor sites and activate themselves in an autocrine manner.…”

“…TAMCs could drive angiogenesis, immunosuppression, as well as tumor invasion and metastasis through secreting substantial proteolytic enzymes and growth factors 79 , 81 . Nevertheless, some studies have shown that a high frequency of TAMCs correlated with better progression-free survival and overall survival 79 , 80 . Together, the immunosuppression of TAMCs in TME remains relatively vague and controversial.…”

Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors

“…The specifics of the tumor microenvironment, such as hypoxia, low pH, and metabolite composition, can then imprint the developing and maturing MCs with a tumor microenvironment-specific activation phenotype, whose impact on the tumor could be hardly inferred from plain numbers of infiltrating MCs and their associations with the disease severity. In addition, mast cells in the tumor microenvironment can be phenotypically/functionally heterogeneous [ 58 ]. MCs heterogeneity was initially described based on their localization and protease content.…”