Ectonucleoside triphosphate diphosphohydrolase 6: A double-edged sword in cancer prognosis and therapy

Abstract

Malignant diseases in both children and adults are a worldwide public health priority with a high socioeconomic burden. Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6) molecule exhibits divergent expression patterns across different cancers. Its increased expression in some tumors may allow them to escape anti-tumor immune responses, potentially by inducing an immunosuppressive tumor microenvironment and favoring a poorer prognosis. Conversely, in vivo, a mutated ENTPD6 gene may induce effective cytotoxic T cell responses, thereby reducing liver tumor size. Additionally, low expression of ENTPD6 has been related to chemotherapy resistance, whereas specific ENTPD6-derived neoepitopes may potentially enhance the efficacy of immunotherapy. This paper analyses the dual roles and clinical utility of ENTPD6 in cancer.

Key Words: Ectonucleoside triphosphate diphosphohydrolase 6; Cancer; Prognosis; Therapy; Antitumor immunity

Core Tip: Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6) has dual effects on cancer development and progression, influencing immune surveillance and immune evasion through tumor microenvironment modulation. It serves as a promising novel molecular biomarker for prognosis and for predicting cancer therapy responses. Furthermore, ENTPD6-derived neopeptide vaccines, as well as adoptive T-cell transfer using T cells engineered with T-cell receptors targeting ENTPD6, may constitute promising strategies in cancer immunotherapy.

TO THE EDITOR

Malignant diseases in both children and adults are a worldwide public health priority with a high socioeconomic burden. Unfortunately, cancer cells often escape innate and adaptive immune responses, particularly T cell-mediated cytotoxicity. Indeed, cancer treatment may also lead to resistance and serious side effects, highly feared by physicians and patients, which need to be determined, effectively managed, and prevented. Even so, this is often not achieved, thus reducing survivorship and quality of life. Recently, Gang et al[1] found that overexpression of ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6) may contribute to tumor progression by modulating purine and pyrimidine metabolism, potentially promoting innate and adaptive immune evasion. This hydrolytic enzyme and its derived peptides are determined mainly using multi-omics platforms, including computational analyses, tetramer staining, and next-generation sequencing[2]. Nevertheless, the role and expression of ENTPD6 are context-dependent, varying within cancer types and tumor microenvironment (TME)[1,3]. The precise mechanisms underlying differences in ENTPD6 expression remain to be elucidated. There are several potential mechanisms responsible for this varying expression, including genetic copy number alterations, DNA methylation, and RNA modifications[1,2]. This letter to the editor will analyze the divergent roles of ENTPD6 in antitumor immunity and cancer therapy response.

DIVERGENT ROLES OF ENTPD6 IN CANCERS

Impact on antitumor immunity: duality of function

There is some evidence that ENTPD6 overexpression in certain tumors promotes an immune-resistant TME, thereby limiting inflammation and anticancer immune responses[1]. It is now well established that dysregulation of cellular processes (e.g., nucleotide, purine, and pyrimidine metabolism) can be reprogrammed by tumor cells in response to metabolic stressors within the TME, leading to the accumulation of immunosuppressive metabolites[4]. This process is thought to be driven by ENTPD6 overexpression[1], although direct causal effects have yet to be experimentally demonstrated. Such a TME promotes exhaustion of antitumor immune cells (e.g., cytotoxic cluster of differentiation 8+ T lymphocytes and natural killer cells) while driving the expansion of immunosuppressive cells (e.g., regulatory T cells and M2 macrophages) and the expression of immune checkpoints (Figure 1)[1,5]. Interestingly, M2-type macrophages and factor forkhead box protein 3 regulatory T lymphocytes have been correlated with a poor prognosis of several malignant diseases, including triple-negative breast cancer, hepatocellular carcinoma (HCC), and lung cancer[6-8]. Moreover, high ENTPD6 expression levels exhibited poorer overall survival outcomes in stomach adenocarcinoma[9]. Poor survival can be due to the immunosuppressive TME created by high ENTPD6 expression, which protects tumor cells from effective antitumor immune responses. Experimental validation, both in vitro and in vivo, is needed to clarify the relationship between immune evasion mechanisms and ENTPD6 expression patterns in cancer.

Figure 1 Ectonucleoside triphosphate diphosphohydrolase 6-a double-edged sword in cancer. ENDP6: Ectonucleoside triphosphate diphosphohydrolase 6; Treg: Regulatory T cells; CTL: Cytotoxic cluster of differentiation 8+ T cells; TCR: T cell receptor; CD: Cluster of differentiation; NK: Natural killer; HLA: Human leukocyte antigen.

In contrast to the data discussed above, there is a body of experimental evidence that argues that ENTPD6 restrains cancer growth and proliferation. Notably, Chen et al[2] demonstrated that a mutated ENTPD6 gene can produce a specific peptide sequence (5’-FYAFSCYYDL-3’) that is presented by human leukocyte antigen (HLA)-A*24:02 molecules on tumor cells in vivo. Interestingly, cytotoxic cluster of differentiation 8+ T lymphocytes identify and eliminate liver tumor cells expressing this immunodominant epitope, thereby reducing the tumor size of HCC (Figure 1)[2].

Impact on cancer therapy response: Duality of effect

Cancer cell resistance to chemotherapeutic agents can be due to several factors, such as low expression of ENTPD6, especially in testicular germ cell tumors and pancreatic cells[3,10]. While the mechanism underlying ENTPD6-associated drug resistance is not yet known, it has been suggested that the interaction between ENTPD6 and E-cadherin may contribute to cisplatin resistance[3]. Conversely, high ENTPD6 expression was significantly associated with resistance to camptothecin[1]. These findings suggest that ENTPD6 may serve as a promising molecular biomarker of chemotherapy resistance and a novel therapeutic target for modulating chemotherapy sensitivity in some solid tumors.

Cancer immunotherapies that activate the immune system have shown remarkable results for many patients. Resistance to immunotherapy can occur in 60%-80% of patients[11]. Several investigations indicate that both tumor cell-extrinsic and tumor cell-intrinsic factors contribute to the resistance mechanisms[11]. Tumor cell-intrinsic factors that contribute to immunotherapy resistance include expression or repression of certain genes and pathways in tumor cells that prevent immune cell infiltration or function within the TME. One reason why a tumor may not respond to immunotherapy is elevated ENTPD6 expression, possibly due to the induction of an immunosuppressive TME[1].

ENTPD6-derived neopeptide vaccines have shown promise, particularly in advanced HCC. Chen et al[2] demonstrated that among the 14 patients with HCC, only one patient expressed a specific peptide sequence 5’-FYAFSCYYDL-3’, identified as a dominant HCC neoantigen. This peptide is presented by HLA-A*24:02, highlighting the need for personalized vaccine design. Although peptide sequence 5’-FYAFSCYYDL-3’ presented by HLA-A*24:02 may trigger an effective cytotoxic antitumor immune response in vivo[2], it remains unclear whether this epitope confers protection against HCC in larger patient cohorts. Adoptive transfer of T cells engineered with T cell receptors (TCRs) or chimeric antigen receptors represents another promising approach in cancer immunotherapy. Using the coordinate human leukocyte antigen peptide affinity system, Chen et al[2] identified the dominant TCR clone S20-1-BA2 specific for ENTPD6 neoantigen, suggesting that this platform can be employed to validate the feasibility and efficacy of TCR-T cell therapy targeting ENTPD6.

CONCLUSION

These findings indicate that there might have been a divergence in the function of ENTPD6 in tumorigenesis and antitumor immunity. Research on ENTPD6-derived peptides as a therapeutic target for cancer is still in its early stages, yet some epitopes previously identified in multi-omics platforms and validated in the coordinate human leukocyte antigen peptide affinity system have shown promise for HCC treatment.