Inflammatory infiltrates in melanocytic lesions / Infiltrados inflamatorios en lesiones melanocíticas

SUMMARY: Inflammatory infiltrates are frequently present in melanocytic lesions, with different distribution and composition. Much attention has been devoted to tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment, establishing their prognostic and predictive value in many malignancies, including melanoma. However, lymphocytes, albeit the most numerous and consistent presence, constitute only part of the immune microenvironment. Other inflammatory cells, including neutrophils, plasma cells, eosinophils and mast cells, are found in melanoma and other melanocytic lesions.Few studies offer a detailed count of these inflammatory infiltrates across the spectrum of melanocytic lesions. By using whole slide image analysis and open source software, in the present study we report the enumeration of different inflammatory infiltrates in benign melanocytic nevi, dysplastic nevi, melanoma in situ and invasive malignant melanomas. Significant higher numbers of plasma cells and neutrophils were observed in melanoma. These results indicate that composition of the inflammatory infiltrate may contribute to the diagnostic algorithm of melanocytic lesions.

RESUMEN: Los infiltrados inflamatorios están presentes con frecuencia en las lesiones melanocíticas, con diferente distribución y composición. Se ha prestado mucha atención a los linfocitos infiltrantes de tumores (TIL) en el microambiente tumoral, estableciendo su valor pronóstico y predictivo en muchas neoplasias malignas, incluido el melanoma. Sin embargo, los linfocitos de presencia más numerosa y constante, constituyen solo una parte del microambiente inmunológico. Otras células inflamatorias, incluidos neutrófilos, células plasmáticas, eosinófilos y mastocitos, se encuentran en el melanoma y otras lesiones melanocíticas. Pocos estudios ofrecen un recuento detallado de estos infiltrados inflamatorios en todo el espectro de lesiones melanocíticas. Mediante el uso de análisis de imágenes de diapositivas completas y software de código abierto, en el presente estudio informamos la enumeración de diferentes infiltrados inflamatorios en nevos melanocíticos benignos, nevos displásicos, melanoma in situ y melanomas malignos invasivos. Se observaron números significativamente más altos de células plasmáticas y neutrófilos en el melanoma. Estos resultados indican que la composición del infiltrado inflamatorio puede contribuir al algoritmo diagnóstico de las lesiones melanocíticas.

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We aimed to determine whether stimulating antigen-presenting cells, including macrophages and dendritic cells, using a CD40 agonist could improve this response. METHODS: We compared treatment responses in subcutaneous, orthotopic, and 2 plasmid-based murine intrahepatic CCA (iCCA) models. Mice were treated for 4 weeks with weekly IgG control, a CD40 agonistic antibody, anti-PD-1, or the combination of both (anti-CD40/PD-1). Flow cytometric (FACS) analysis of lymphocytes and myeloid cell populations (including activation status) was performed. We used dendritic cell knockout mice, and macrophage, CD4+ and CD8+ T cell depletion models to identify effector cells. Anti-CD40/PD-1 was combined with chemotherapy (gemcitabine/cisplatin) to test for improved therapeutic efficacy. RESULTS: In all 4 models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 therapy led to a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4+ and CD8+ T cells, natural killer cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Depletion of macrophages, dendritic cells, CD4+ T cells, or CD8+ T cells abrogated treatment efficacy. Combining anti-CD40/PD-1 with gemcitabine/cisplatin resulted in a significant survival benefit compared to gemcitabine/cisplatin alone. CONCLUSION: CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance the efficacy of first-line chemotherapy. LAY SUMMARY: Checkpoint inhibition, a common form of immune therapy, is generally ineffective for the treatment of cholangiocarcinoma. These tumors suppress the infiltration and function of surrounding immune cells. Stimulating immune cells such as macrophages and dendritic cells via the CD40 receptor activates downstream immune cells and enhances the response to checkpoint inhibitors.

Correlation of MET and PD-L1 Expression in Malignant Melanoma.

The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, programmed death-ligand 1 (PD-L1), with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions, and in a human melanoma tissue microarray containing one hundreds melanocytic lesions, including primary cutaneous melanomas, primary mucosal melanomas, metastatic melanomas and benign melanocytic nevi as controls. After color deconvolution, each core was segmented to isolate staining and calculate the percentage of positive cells. Overall, MET expression was higher in tumors with increased PD-L1 expression. Moreover, a robust correlation between MET and PD-L1 expression was found in samples from metastatic melanoma and not in primary cutaneous or mucosal melanoma. These data suggest that relative expression levels of these proteins in combination is a marker of advanced disease and testing for expression of these markers should be considered in patients with melanoma.