Targeting adenosine in cancer immunotherapy to enhance T-cell function
- 1Ludwig Institute for Cancer Research Lausanne, Department of Oncology, Université de Lausanne, Switzerland
- 2Lausanne University Hospital (CHUV), Switzerland
- 3Centre Léon Bérard, INSERM U1052 Centre de Recherche en Cancerologie de Lyon, France
T cells play a critical role in cancer control, but a range of potent immunosuppressive mechanisms can be upregulated in the tumor microenvironment (TME) to abrogate their activity. While various immunotherapies (IMTs) aiming at re-invigorating the T-cell-mediated anti-tumor response, such as immune checkpoint blockade (ICB), and the adoptive cell transfer (ACT) of natural or gene-engineered ex vivo expanded tumor-specific T cells, have led to unprecedented clinical responses, only a small proportion of cancer patients benefit from these treatments. Important research efforts are thus underway to identify biomarkers of response, as well as to develop personalized combinatorial approaches that can target other inhibitory mechanisms at play in the TME. In recent years, adenosinergic signaling has emerged as a powerful immuno-metabolic checkpoint in tumors. Like several other barriers in the TME, such as the PD-1/PDL-1 axis, CTLA-4, and indoleamine 2,3-dioxygenase (IDO-1), adenosine plays important physiologic roles, but has been co-opted by tumors to promote their growth and impair immunity. Several agents counteracting the adenosine axis have been developed, and pre-clinical studies have demonstrated important anti-tumor activity, alone and in combination with other IMTs including ICB and ACT. Here we review the regulation of adenosine levels and mechanisms by which it promotes tumor growth and broadly suppresses protective immunity, with extra focus on the attenuation of T cell function. Finally, we present an overview of promising pre-clinical and clinical approaches being explored for blocking the adenosine axis for enhanced control of solid tumors.
Keywords: Adenosine, cAMP, CD73, CD39, cancer immuno therapy, T cells, Tumor microenviroment
Received: 12 Jan 2019;
Accepted: 10 Apr 2019.
Edited by:Anil Shanker, Meharry Medical College, United States
Reviewed by:Per Thor Straten, Herlev Hospital, Denmark
Mikhail M. DIkov, Wexner Medical Center, The Ohio State University, United States
Copyright: © 2019 Vigano, Alatzoglou, Irving, Ménétrier-Caux, Caux, Romero and Coukos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. George Coukos, Université de Lausanne, Ludwig Institute for Cancer Research Lausanne, Department of Oncology, Lausanne, 1015, Vaud, Switzerland, firstname.lastname@example.org