Adenosine signaling: Optimal target for gastric cancer immunotherapy

Abstract

Gastric cancer (GC) is one of the most common malignancy and leading cause of cancer-related deaths worldwide. Due to asymptomatic or only nonspecific early symptoms, GC patients are usually in the advanced stage at first diagnosis and miss the best opportunity of treatment. Immunotherapies, especially immune checkpoint inhibitors (ICIs), have dramatically changed the landscape of available treatment options for advanced-stage cancer patients. However, with regards to existing ICIs, the clinical benefit of monotherapy for advanced gastric cancer (AGC) is quite limited. Therefore, it is urgent to explore an optimal target for the treatment of GC. In this review, we summarize the expression profiles and prognostic value of 20 common immune checkpoint-related genes in GC from Gene Expression Profiling Interactive Analysis (GEPIA) database, and then find that the adenosinergic pathway plays an indispensable role in the occurrence and development of GC. Moreover, we discuss the pathophysiological function of adenosinergic pathway in cancers. The accumulation of extracellular adenosine inhibits the normal function of immune effector cells and facilitate the effect of immunosuppressive cells to foster GC cells proliferation and migration. Finally, we provide insights into potential clinical application of adenosinergic-targeting therapies for GC patients.

Keywords: CD39; CD73; adenosine; gastric cancer; immunotherapy.

Figure 1

The analysis of immune checkpoint-related genes expression in GC by GEPIA database. The results revealed that 9 genes were confirmed to have significant differential expression in GC compared to the normal tissues. Among them, higher expression was observed in HHLA2, ENTPD1, PVR, CD24, NT5E, TIGIT, CD276, and CD47 and lower expression was observed in LGALS9C. Red color represents tumor tissue (n=408), and gray color represents normal tissue (n=211). STAD, stomach adenocarcinoma. * P < 0.05.

Figure 2

Kaplan-Meier survival curves comparing the high and low expression of immune checkpoint-related genes in GC by GEPIA database. The results showed that only the high expression of NT5E (encode CD73) was correlated with poor prognosis of GC patients (p<0.05). The red line indicates the high expression group of genes (n=192) and the blue line represents the low expression group of genes (n=191).

Figure 3

The analysis of adenosinergic pathway-related genes expression in GC by GEPIA database. (A) The risk assessment of 20 common immune checkpoint-related genes affecting the prognosis of GC patients. By comparing the survival contribution of multiple genes via Mantel-Cox test, we found that NT5E (encode CD73) showed the most obvious detrimental role in GC patients (n=383). (B) The expression levels of ENTPD1 and NT5E in different tumor stages of GC. With the progression of GC, the expression of ENTPD1 and NT5E also increased. (C) The expression levels of adenosine receptors in GC patients. The analysis showed that only ADORA2B expression (encode A2BR) increased in GC compared to the normal tissues and only ADORA2A (encode A2AR) was positively correlated with the progression of GC. Red color represents tumor tissue (n=408), and gray color represents normal tissue (n=211). STAD, stomach adenocarcinoma; HR, hazard ratio. * P < 0.05.

Figure 4

Immune regulation of adenosine signaling in the TME. Cell stress promotes eATP production and contributes to chronic inflammation via P2Rs. Within the TME, accumulated eATP can be degraded to ADO by the sequential action of the ectonucleotidases CD39 and CD73 or other alternative pathways such as ALP or PAP-mediated process. In addition, the sequential catabolism of NAD⁺ by CD38, CD203a and CD73 also can generate ADO and the high concentration of intracellular ADO can be transported outside the cell via ENTs or CNTs to maintain balance. The bioavailability of extracellular ADO is regulated by adenosine-converting enzymes such as ADK and ADA, which converts ADO into AMP and inosine respectively. High concentrations of ADO binding to adenosine receptors to inhibit the activation of immune cells and stimulate immunosuppressive cells to promote the immune escape of cancers. eATP, extracellular adenosine triphosphate; eAMP, extracellular adenosine monophosphate; NK cell, natural killer cell; DC, dendritic cell; Treg, regulatory T cell; TAM, tumor-associated macrophage; CAF, cancer associated fibroblast; MDSC, myeloid-derived suppressor cell; MSC, mesenchymal stromal cell; ADO, adenosine; NAD⁺, nicotinamide adenine dinucleotide; ADPR, adenosine diphosphate ribose; ADA, adenosine deaminase; ADK, adenosine kinase; ENT, equilibrative nucleoside transporter; CNT, concentrative nucleoside transporter; P2Rs, P2 purinergic receptors; PAP, prostatic acid phosphatase; ALP, alkaline phosphatase; cAMP, cyclic adenosine monophosphate.