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

SIMPLE SUMMARY: During the fight against tumor, some cells of the immune system such as cytotoxic lymphocytes eliminate tumoral cells while others such as tumor-associated macrophages favor tumor development. Mast cells (MCs) are multifaceted immune cells whose role in cancer is still poorly understood. Moreover, MCs are poorly characterized in the context of cancer and their presence in the tumor microenvironment has been reported to be either associated with good or bad prognosis. In this pilot study we characterized tumor-associated MCs (TAMCs) in lung cancer. We showed that TAMCs exhibited a typical phenotype and can be classified in two subsets according to alphaE integrin (CD103) expression. CD103(+) TAMCs appeared more mature, more prone to interact with CD4(+) T cells, and located closer to cancer cells than their CD103(−) counterpart. This study revealed that a high frequency of total TAMC correlated with better overall survival and progression free survival in patients and underlined MC heterogeneity in 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.