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Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy

Authors Robainas M, Otano R, Bueno S, Ait-Oudhia S

Received 16 January 2017

Accepted for publication 1 March 2017

Published 23 March 2017 Volume 2017:10 Pages 1803—1807

DOI https://doi.org/10.2147/OTT.S132508

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr William Cho

Marianela Robainas, Rafael Otano, Stephen Bueno, Sihem Ait-Oudhia

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA

Abstract:
Autophagy is a vital, physiological catabolic process for cell survival by which cells clear damaged organelles and recycle nutrients when homeostasis is maintained. Cancer is a complex disease with uncontrolled growth of cancer cells. Recent studies have suggested the role of autophagy in cancer. A complex relationship exists between autophagy and cancer, since autophagy can contribute to the survival or the destruction of malignant cells depending on the stage of tumor development. In this review, we describe in detail the mechanism underlying autophagy in cancer cells and the intricate involvement of the programmed cell death-1 (PD1) receptor with its ligand (PD-L1). The overexpression of PD-L1 receptors on cancer cell membranes has been observed in several types of cancers. The interaction of PD-L1 on cancer cells with PD1 on the surface of T-cells causes cancer cells to escape from the immune system by preventing the activation of new cytotoxic T-cells in the lymph nodes and subsequent recruitment to the tumor. In addition to its immunopathogenicity, PD1 has been related to autophagy. Reduction of this receptor due to treatment increases autophagy, therefore promoting the recycling of nutrients and clearance of toxic species, consequently promoting cell survival. In addition, PD-L1/PD1 engagement can induce autophagy in nearby T-cells due to a decrease in the amino acids tryptophan and arginine and due to the deprivation of nutrients such as glucose followed by a reduction in glucose metabolism. Resistance to cancer therapies is attributed to various pathways in oncogenesis including, inhibition of tumor suppressors, alteration of the tumor metabolic environment, and upregulation of autophagy. Here we explore the interaction between the immunosuppressive PD-L1/PD1 engagement and autophagy mechanisms, and evaluate the impact of inhibition of these pathways in augmenting antitumor efficacy.

Keywords: immuno-oncology, cancer immunotherapy, autophagy, PD1, PD-L1

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