Person:

Kubler, Kirsten

Vulvar cancer is rare but incidence rates are increasing due to an aging population and higher frequencies of young women being affected. In locally advanced, metastatic or recurrent disease prognosis is poor and new treatment modalities are needed. Immune checkpoint blockade of the PD-1/PD-L1 pathway is one of the most important advancements in cancer therapy in the last years. The clinical relevance of PD-L1 expression in vulvar cancer, however, has not been studied so far. We determined PD-L1 expression, numbers of CD3+ T cells, CD20+ B cells, CD68+ monocytes/macrophages, Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages by immunohistochemistry in 103 patients. Correlation analysis with clinicopathological parameters was undertaken; the cause-specific outcome was modeled with competing risk analysis; multivariate Cox regression was used to determine independent predictors of survival. Membranous PD-L1 was expressed in a minority of tumors, defined by HPV-negativity. Its presence geographically correlated with immunocyte-rich regions of cancer islets and was an independent prognostic factor for poor outcome. Our data support the notion that vulvar cancer is an immunomodulatory tumor that harnesses the PD-1/PD-L1 pathway to induce tolerance. Accordingly, immunotherapeutic approaches might have the potential to improve outcome in patients with vulvar cancer and could complement conventional cancer treatment.

How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA-sequencing data from ~6,700 samples across 29 normal tissues reveals multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We confirm that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, suggesting that environmental factors can promote somatic mosaicism. Mutation burden is associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over time and number of cell divisions. Finally, we find that normal tissues harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as the basis to associate clonal expansion with environmental factors, aging and risk of disease.