CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Abstract

CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

Gastric metabolomics analysis supportsH. pylori’s catabolism of organic and amino acids in both the corpus and antrum

“…Taken together, the metabolomics supports the idea that the corpus is undergoing atrophy, a known H. pylori-associated condition (39), and indeed that released phospholipids may be early indicators of carcinogenesis (40). Adenosine has immunosuppressive properties, and also has been associated with cancer development (41,42). Thus the data might suggest that the H. pylori mouse model develops signs of carcinogenesis, cell damage, immunosuppression that can be detected using metabolomics.…”

Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

“…For example, A 2A R is upregulated during inflammation on effector T cells and inhibits T cell proliferation, cytotoxic activity and cytokine production, while activation in T reg promotes their expansion and immunosuppressive activity. A 2A R activation on natural killer cells inhibits their maturation, proliferation, activation, and secretion of cytotoxic cytokines [6,151]. Nevertheless, with respect to PDAC, finer resolution of A 2A and A 2B expression in TME, i.e., in cancer vs immune cells, will be required to understand survival curves (see above) and determine whether A 2A R is immunosuppressive and will constitute a successful target in ongoing clinical trials (Table 1).…”

The Adenosine System at the Crossroads of Intestinal Inflammation and Neoplasia

“…In line with this view, several clinical trials are currently in progress to evaluate the putative beneficial effect of pharmacological tools acting on adenosine system alone or in combination in the management of neoplastic disorders [ 120 ]. For instance, clinical trials are underway for AB928, a dual A 2A /A 2B receptor antagonist, combined with chemotherapy in CRC patients [ 121 ]. Other clinical trials in phase 1/2a are underway to assess the safety and efficacy of a monoclonal antibody that inhibit CD73, MEDI9447, combined with chemotherapy and radiotherapy in patients with advanced solid tumors, including CRC [ 121 ].…”

“…For instance, clinical trials are underway for AB928, a dual A 2A /A 2B receptor antagonist, combined with chemotherapy in CRC patients [ 121 ]. Other clinical trials in phase 1/2a are underway to assess the safety and efficacy of a monoclonal antibody that inhibit CD73, MEDI9447, combined with chemotherapy and radiotherapy in patients with advanced solid tumors, including CRC [ 121 ]. At present, the development of inhibitors of CD39 for cancer therapy is underway, but none have yet entered the clinic.…”