Tumor-Associated Lymphatics Upregulate MHC-II to Suppress Tumor-Infiltrating Lymphocytes.

Steady-state lymphatic endothelial cells (LECs) can induce peripheral tolerance by presenting endogenous antigens on MHC class I (MHC-I) molecules. Recent evidence suggests that lymph node LECs can cross-present tumor antigens on MHC-I to suppress tumor-specific CD8+ T cells. Whether LECs can act as immunosuppressive cells in an MHC-II dependent manner in the local tumor microenvironment (TME) is not well characterized. Using murine heterotopic and spontaneous tumor models, we show that LECs in the TME increase MHC-II expression in the context of increased co-inhibitory signals. We provide evidence that tumor lymphatics in human melanoma and breast cancer also upregulate MHC-II compared to normal tissue lymphatics. In transgenic mice that lack LEC-specific MHC-II expression, heterotopic tumor growth is attenuated, which is associated with increased numbers of tumor-specific CD8+ and effector CD4+ T cells, as well as decreased numbers of T regulatory CD4+ cells in the TME. Mechanistically, we show that murine and human dermal LECs can take up tumor antigens in vitro. Antigen-loaded LECs in vitro can induce antigen-specific proliferation of CD8+ T cells but not CD4+ T cells; however, these proliferated CD8+ T cells have reduced effector function in the presence of antigen-loaded LECs. Taken together, our study suggests LECs can act as immunosuppressive cells in the TME in an MHC-II dependent manner. Whether this is a result of direct tumor antigen presentation on MHC-II requires additional investigation.

Treatment of Patients with Malignant Peritoneal Mesothelioma.

Malignant peritoneal mesothelioma is a rare malignancy arising from the serosa of the peritoneal cavity. It is diagnosed based on suspicious findings on cross sectional imaging and a tissue biopsy showing confirmatory histologic and immunohistochemical features. The disease is hallmarked by its propensity to progress mainly in the peritoneal cavity. In selected patients, surgical cytoreduction and hyperthermic intra-operative peritoneal chemotherapy has become the initial preferred treatment and is associated with provide prolonged in many patients. Systemic chemotherapy using a couplet of cisplatin or gemcitabine with pemetrexed has modest response rates and duration of response. Expression of PD-L1 has been demonstrated in peritoneal mesothelioma tumors and there has been significant interest in the use of check point blockade targeted against PD-L1 in this clinical setting. Future clinical research using a combination of check point blockade with surgical cytoreduction is a high clinical priority.

Lymphatics in Tumor Progression and Immunomodulation.

The lymphatic system consists of a unidirectional hierarchy of vessels responsible for fluid homeostasis, lipid absorption, and the transport of immune cells and antigens to secondary lymphoid organs. In cancer, lymphatics play complex and heterogenous roles that can promote or inhibit tumor growth. While lymphatic proliferation and remodeling promote tumor dissemination, functional lymphatics are necessary for generating an effective immune response. Recent reports have noted lymphatic-dependent effects on the efficacy of immunotherapy. These findings suggest that the impact of lymphatic vessels on tumor progression is organ- and context-specific and that a greater understanding of the interaction of tumor cells, lymphatics, and the tumor microenvironment can unveil novel therapies.

Histopathologic Features of Lymphedema: A Molecular Review.

An estimated 5 million people in the United States are affected by secondary lymphedema, with most cases attributed to malignancies or malignancy-related treatments. The pathogenesis of secondary lymphedema has historically been attributed to lymphatic injury or dysfunction; however, recent studies illustrate the complexity of lymphedema as a disease process in which many of its clinical features such as inflammation, fibrosis, adipogenesis, and recurrent infections contribute to on-going lymphatic dysfunction in a vicious cycle. Investigations into the molecular underpinning of these features further our understanding of the pathophysiology of this disease and suggests new therapeutics.