ABSTRACT
Mast cell infiltration of tumour islets represents a survival advantage in non-small cell lung cancer (NSCLC). The phenotype and activation status of these mast cells is unknown. We investigated the mast cell phenotype in terms of protease content (tryptase-only [MCT], tryptase + chymase [MCTC]) and tumour necrosis factor-alpha (TNFα) expression, and extent of degranulation, in NSCLC tumour stroma and islets. Surgically resected tumours from 24 patients with extended survival (ES; mean survival 86.5 months) were compared with 25 patients with poor survival (PS; mean survival 8.0 months) by immunohistochemistry. Both MCT and MCTC in tumour islets were higher in ES (20.0 and 5.6 cells/mm2 respectively) compared to PS patients (0.0 cells/mm2) (p < 0.0001). Both phenotypes expressed TNFα in the islets and stroma. In ES 44% of MCT and 37% of MCTC expressed TNFα in the tumour islets. MCT in the ES stroma were more degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p = 0.0022), and ES islet mast cells (2.24 compared to 1.71, p < 0.0001). Since both MCT and MCTC infiltrating tumour islets in ES NSCLC patients express TNFα, the cytotoxic activity of this cytokine may confer improved survival in these patients. Manipulating mast cell microlocalisation and functional responses in NSCLC may offer a novel approach to the treatment of this disease.
Subject(s)
Carcinoma, Non-Small-Cell Lung/immunology , Chymases/genetics , Lung Neoplasms/immunology , Mast Cells/immunology , Tryptases/genetics , Tumor Necrosis Factor-alpha/genetics , Aged , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Cell Degranulation , Cell Movement , Chymases/immunology , Cytotoxicity, Immunologic , Female , Gene Expression , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Mast Cells/pathology , Middle Aged , Phenotype , Survival Analysis , Tryptases/immunology , Tumor Necrosis Factor-alpha/immunologyABSTRACT
There is a marked survival advantage for patients with nonsmall cell lung cancer (NSCLC) expressing high numbers of macrophages in their tumour islets. The primary aim of the present study was to determine the immunological phenotype of NSCLC-associated macrophages. CD68(+) macrophages expressing markers of a cytotoxic M1 phenotype or a noncytotoxic M2 phenotype were identified in the islets and stroma of surgically resected tumours from 20 patients with extended survival (median 92.7 months) and 20 with poor survival (median 7.7 months), using immunohistochemistry. The islet density of both M1 and M2 macrophages was markedly increased in extended compared with poor survival patients. In the extended survival group, M1 islet density was significantly increased compared with M2 density, 70% of islet macrophages were positive for M1 markers versus 38% for M2, and the islet:stromal ratio of M1 macrophages was markedly increased compared with M2. The 5-yr survival for patients with above and below median expression of M1 macrophages in the islets was >75 and <5%, respectively. Macrophages infiltrating the tumour islets in nonsmall cell lung cancer were predominantly of the M1 phenotype in patients with extended survival. The survival advantage conferred by islet macrophage infiltration may be related to their cytotoxic antitumour activity.
