Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling

Martins C, Rasbach E, Heppt MV, Singh P, Kulcsar Z, Holzgruber J, Chakraborty A, Mucciarone K, Kleffel S, Brandenburg A, Hoetzenecker W, Rahbari NN, DeCaprio JA, Thakuria M, Murphy GF, Ramsey MR, Posch C, Barthel SR, Schatton T (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Science Advances American Association for the Advancement of Science

Book Volume: 10

Pages Range: eadi2012-

Journal Issue: 3

DOI: 10.1126/sciadv.adi2012

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.

Involved external institutions

Veterans Affairs Healthcare System Boston and Harvard Medical School US United States (USA) (US) Johannes Kepler Universität (JKU) Linz AT Austria (AT) Universitätsklinikum Mannheim DE Germany (DE)

How to cite

APA:

Martins, C., Rasbach, E., Heppt, M.V., Singh, P., Kulcsar, Z., Holzgruber, J.,... Schatton, T. (2024). Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling. Science Advances, 10(3), eadi2012-. https://dx.doi.org/10.1126/sciadv.adi2012

MLA:

Martins, Christina, et al. "Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling." Science Advances 10.3 (2024): eadi2012-.

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