Abstract
Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies.Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients’ prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma.
Highlights
Over the last few years, oncology research is increasingly focused on the understanding of mutual interactions between cancer, stromal and immune cells in the tumor microenvironment (TME)
The appearance of metastases in patients with squamous-cell carcinoma (sSCC) has recently been associated with increased intratumoral lymphatic vessel density (LVD) [24] but it remains unknown whether the abundance of lymphatic vessels correlates with immune cell infiltration in the tumor
Similar to previous data in melanoma [5], we found an increased frequency of intratumoral CD8+ T cells in sSCC with high Lymphatic endothelial cell (LEC) density, there was in contrast to melanoma no significant positive correlation between LECs and CD8+ T cells
Summary
Over the last few years, oncology research is increasingly focused on the understanding of mutual interactions between cancer, stromal and immune cells in the tumor microenvironment (TME). Immune cells have been shown to play various roles impacting tumor progression, metastasis formation and responsiveness to chemo- and immunotherapies [1,2,3]. A major characteristic of many tumors in both humans and mice is the proliferation and activation of lymphatic endothelial cells (LECs) within the primary tumor, as well as in pre-metastatic and metastatic sites [4,5,6]. The resulting increased lymphatic vessel density (LVD) correlates with tumor metastasis formation in murine models of melanoma, breast and pancreatic cancers [7]. Lymphatic vessels offer a route for cancer cells to disseminate, enhanced by secretion of different chemokines such as CCL21 www.oncotarget.com that actively supports tumor cell invasion into lymphatic vessels and promotes lymph node (LN) metastases [8]
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