Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

Abstract

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: CD39; CD73; T cells; adenosine; cAMP; cancer immunotherapy; tumor microenvironment.

Figure 1

Regulation of interstitial adenosine levels in injured tissue. Stress-induced, extracellular buildup of ATP or NAD⁺ fuels catabolic adenosine-generating pathways, such as the one mediated by CD39 and CD73. The activity of other ecto-nucleotidases including CD38, CD203a, ALP, and PAP, also contribute toward extracellular adenosine accumulation. Adenosine can also be produced intracellularly by SAHH-exerted hydrolysis of SAH, as well as by soluble CD73-mediated catabolism of AMP, and it can be exported by ENTs in a diffusion-limited manner. On the flip side, the combination of CD26-bound ADA activity and of adenosine cellular uptake, either through equilibrative ENTs or via concentrative CNTs, limits interstitial adenosine levels. Intracellularly, adenosine can be eliminated via its conversion to SAH by SAHH, to AMP by ADK, or to inosine by ADA. SAHH, S-adenosylhomocysteine hydrolase; SAH, S-Adenosylhomocysteine; ENTs, equilibrative nucleoside transporters; CNTs, concentrative nucleoside transporters; ADK, adenosine kinase; ADA, adenosine deaminase.

Figure 2

Overview of the pleiotropic effects of adenosine in the TME. Adenosine enables tumor cells to escape immune-surveillance by limiting the functionality of multiple potentially protective immune infiltrates including T cells, DCs, NK cells, macrophages and neutrophils, while enhancing the activity of immunosuppressive cell-types, such as MDSCs and Tregs. In addition, adenosine not only assists tumor cells in co-opting adjacent fibroblasts for support, but also induces the formation of new blood vessels. Adenosine also affects the capacity of some tumor cell-types to survive, proliferate, migrate and invade neighboring tissues (HPC, bone marrow-derived hematopoietic progenitor cells).

Figure 3

Approaches for blocking adenosinergic signaling in the TME. The inhibitory effects of adenosine in the TME can be circumvented by administration of mAbs or small molecules that target enzymes involved in the catabolism of ATP and NAD, such as CD39,CD73 and CD38, as well as by pharmacologic antagonists of A2AR and A2BR to block adenosine-mediated signaling. Whereas multiple such mAbs and pharmacologic inhibitors/antagonists display antitumor activity within murine models of solid tumors (Tables 1, 2), depicted are only those currently evaluated in patients with solid tumor malignancies (Table 3). Finally, treatments that reduce the extracellular export of ATP, such as oxygenation to reverse hypoxia, can attenuate adenosinergic signaling.