POSCHLAB

Merkel Cell Carcinoma (MCC) is a rare, but highly aggressive neuroendocrine cancer of the skin. An antibody that target the immune checkpoint programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) have emerged as effective cancer therapies. Immune checkpoints are crucial regulatory pathways that maintain immune homeostasis via inhibition of pathogenic immune effector responses. Cancer exploits immune checkpoints to evade antitumor immunity. PD-1 pathway interference demonstrates unprecedented response rates in patients with solid tumors. Yet, the majority of patients still do not respond. Because the mechanisms underlying PD-1/PD-L1-driven tumorigenesis are incompletely understood, clinical response to PD-1 pathway blockade is difficult to predict.

PD-1 expression is commonly thought to be confined to immune cells whereas anti-PD-L1 is thought to be primarily expressed by tumor cells. Anti-PD-1 and anti-PD-L1 therapy is believed to activate antitumor immunity by releasing the PD-1 pathway-mediated break on immune effector function. However, PD-1 is not only expressed by immune cells but also by cancer cells. The tumor-cell intrinsic role of the PD-1 receptor and its ligand PD-L1 on MCC cells are unknown.

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Our preliminary data confirms that PD-1 and PD-L1 are expressed by MCC cells. Expression levels are higher than found in other cancers. Thus we hypothesize, that PD-1 and PD-L1 antibody therapy might not only (re-)activate immune-cell mediated tumor cell clearance, but also blocks MCC cell growth by direct PD-1 and PD-L1 interference on MCC cells. This notion is supported by first data showing that targeting of MCC-expressed PD-1 suppresses in vivo tumor growth, even in mice lacking functional immunity.

We aim to 1) characterize MCC-expressed PD-1 and PD-L1 specific signaling interactions underlying cancer progression, and 2) to evaluate the significance of MCC-PD-1 and MCC-PD-L1 and their downstream mediators as predictors of MCC progression and response to PD-1 inhibition.