Protein tyrosine phosphatase nonreceptor 2: A New biomarker for digestive tract cancers

Abstract

In this editorial, the roles of protein tyrosine phosphatase nonreceptor 2 (PTPN2) in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal (GI) cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology. PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity. Accordingly, early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction. On the other hand, recent studies have indicated that PTPN2 has many different roles in different cancer types, which is associated with the complexity of its regulatory network. PTPN2 dephosphorylates and inactivates EGFR, SRC family kinases, JAK1 and JAK3, and STAT1, STAT3, and STAT5 in cell type- and context-dependent manners, which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype. While PTPN2 has been suggested as a potential therapeutic target in cancer treatment, to the best of ourknowledge, no clear treatment protocol has referred to PTPN2. Although there are only few studies that investigated PTPN2 expression in the GI system cancers, which is a potential limitation, the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors, especially in tumors resistant to therapy.

Key Words: Protein tyrosine phosphatase nonreceptor 2; Digestive tract cancers; Gastrointestinal cancer; Biomarker

Core Tip: Protein tyrosine phosphatase nonreceptor 2 (PTPN2) is a member of the protein tyrosine phosphatase family of signaling proteins. Numerous studies have examined the roles of this molecule in antitumor immunity and therapy because of its significant effects on a wide range of events, including the production and distribution of immune cells and numerous pathways that are important to the behavior and treatment of cancers. The role of PTPN2 in gastrointestinal (GI) cancers has been investigated in a limited number of studies, indicating that PTPN2 has heterogeneous effects on different tumors and even on the same type of GI cancer. Currently, this situation limits the recommendation of PTPN2 as a potential biomarker for predicting cancer prognosis and the efficacy of immunotherapy necessitates further studies in GI tumors.

INTRODUCTION

Protein tyrosine phosphatase nonreceptor 2 (PTPN2) is a member of the PTPN family, the largest family of class I cysteine protein tyrosine phosphatases (PTP). Numerous studies have shown that PTPN2 is involved in many biological processes by dephosphorylating many substrate proteins, including EGFR, IR, JAK1, STAT1, STAT3, and SRC family kinases[1]. Moreover, numerous studies on the activity of PTPN2 in immunomodulation have revealed its participation in the pathogenesis of several immune and inflammatory disorders[2-4]. In addition, relationships between PTPN2 and oncogenesis and tumor progression have been demonstrated[5,6]. Importantly, it has been noted that this protein can have adverse functions in different malignancies owing to its multifaceted effects, which depend on the ability of PTPN2 to control many signaling pathways. Therefore, the role of this protein in oncogenesis and its prognostic potential for tumor behavior should be assessed separately in each type of cancer[7].

The activities of PTPN2, a protein with complex roles in cancer, and its potential as a therapeutic target in relation to gastrointestinal (GI) malignancies are covered in this editorial.

GENERAL OVERVIEW OF PTPN2

PTPN2 is an expressed tyrosine phosphatase that is encoded by the namesake gene located on chromosome 18. PTPN2 was first cloned from a human T-cell cDNA library, and accordingly, it is also referred to as T-cell PTP[7,8]. However, subsequent studies have shown that PTPN2 expression is not restricted to T cells and can be detected in many other cell types[9]. Owing to alternative splicing, PTPN2 is expressed in humans as two functional versions, 45- and 48-kDa proteins. While the smaller protein is found mainly in the nucleus and can be transferred to the cytoplasm, the larger protein resides in the endoplasmic reticulum. PTPN2 belongs to the PTP family of signaling proteins, which may be involved in the mitotic cycle, oncogenic transformation, and cell proliferation and differentiation. Therefore, it controls several physiological and pathological processes by removing phosphate groups from receptor protein tyrosine kinases[8]. The substrates of PTPN2 include EGFR, CDF1R, PDGFR, and IR, as well as nonreceptor tyrosine kinases such as JAK, SRC, and STAT family kinases. Various regulatory mechanisms of PTPN2 are intricately connected to pathological events, such as the inflammatory response, immunological response, and tumor growth. PTPN2 influences numerous pathways to modulate the onset, progression, and decrease of inflammatory reactions via many mechanisms that impact the epithelial barrier integrity, inflammatory molecules, and different signaling pathways in immune cells involved in inflammation[10-12].

The functions of PTPN2 in T-cell lineage immune cells have been extensively studied, and its implications for early activation, expansion, survival, differentiation, and regulation of cell subsets have been found to be diverse. The effects of PTPN2 include negative regulation of IL-7R/STAT signaling, dephosphorylation of TCR proximal kinases, and disruption of early developmental checkpoints in T cells. PTPN2 also has essential functions in regulating other immune cells, including dendritic cells[13].

In lymphopenia-induced proliferation, which is a disorder that plays a role in the development of inflammatory bowel illness, rheumatoid arthritis, and type 1 diabetes, several types of T lymphocytes expand as a result of recognizing self-antigens and/or cytokines, especially IL-7[8]. PTPN2 plays a significant role in this process, as it is highly active in naive T cells that exit the thymus. Increased expression of PTPN2 helps regulate the proliferation of T cells and prevents excessive reactions to self-antigens in peripheral tissues. In contrast, a lack of PTPN2 causes an increased immune response that is dependent on the T-cell receptor, leading to the progression of autoimmunity. Consequently, the inhibitory effect of PTPN2 on T cells is crucial for preventing the emergence of autoimmune and inflammatory conditions[8]. According to genome-wide association studies, loss-of-function single-nucleotide polymorphisms in the PTPN2 gene have been linked to an increased risk of developing immunological diseases and inflammatory bowel disorders. The observations of PTPN2-deficient animals that died from acute colitis and systemic inflammation after birth and the increased risk of developing chronic inflammatory illnesses with loss of function also emphasize the anti-inflammatory function of PTPN2. Recently, PTPN2 was shown to affect intestinal inflammation by controlling the function of the intestinal barrier, the levels of inflammatory factors, and/or the behavior of inflammatory immune cells[14].

Although the involvement of PTPN2 in the pathogenesis of nonneoplastic diseases suggests that it may be a potential therapeutic target, the abundant data showing that the domains of action of PTPN2 are sophisticated and that it acts through more than a single pathway should not be ignored. For example, studies have demonstrated that abnormal PTPN2 expression in epithelial cells contributes to many diseases through different mechanisms, such as STAT1/claudin-2 signaling in inflammatory bowel disease, p38/NF-κB signaling in renal cell damage, and JAK/STAT signaling in diabetic periodontitis. Furthermore, an anti-PTPN2 antibody inhibited atherosclerosis in APOE^−/− mice by inhibiting the p65/p38/STAT3 signaling pathway. In addition, PTPN2 influences T-cell functions, including cell proliferation and IFN-γ production, through the JAK/STAT signaling pathway[8,15].

PTPN2 IN CANCER

The considerable effects of PTPN2 on a broad spectrum of events, from the production to the distribution of immune cells, and on many pathways that play crucial roles in the behavior and therapy of cancers, have led to many studies investigating the roles of this molecule in antitumor immunity and therapy. Tumors can protect themselves from the destructive effects of the immune response by both evading immune recognition and inducing an immunosuppressive tumor microenvironment (TME), and the roles of PTPN2 in these contexts have been investigated[5,16] (Figure 1).

Figure 1 Protein tyrosine phosphatase nonreceptor 2 gene mutations and gene expressions. A: Tumors with protein tyrosine phosphatase nonreceptor 2 (PTPN2) mutations according to The Cancer Genome Atlas. Gastrointestinal (GI) cancers are marked with arrows; B: Distribution of PTPN2 gene expression in GI cancers and adjacent tissues according to GEPIA data. ESCA: Esophageal cancers; STAD: Stomach adenocarcinomas; COAD: Colon adenocarcinoma; LIHC: Liver hepatocellular carcinoma; Chol: Cholangiocarcinoma; PAAD: Pancreatic Adenocarcinoma.

Previous studies have indicated that PTPN2 deficiency increases the expression of human leukocyte antigens, which leads to reduced immune evasion of tumor cells through the presentation of more antigens and facilitates tumor cell detection by promoting the production and secretion of T-cell effector molecules, including TNF-α and INF-γ. Moreover, PTPN2 inhibition results in the proliferation of T cells, leading to either CD4+ Th1 cell activation or an increase in the cytotoxicity of CD8+ T cells, which results in an augmented immune response and amelioration of tumor management. These findings support the contribution of PTPN2 to tumor immune escape and the induction of an immunosuppressive TME[8].

As noted above, the effect of PTPN2 on tumor immunity is not limited to only T cells. This protein also influences other immune cells. The absence of PTPN2 increases the killing ability of natural killer (NK) cells and leads to the production of the proinflammatory cytokines IL-1β and IL-18 through inflammasomes in macrophages. The latter has the potential to improve antitumor immunity by stimulating the development of IFN-γ-positive cells, attracting proinflammatory phagocytes and facilitating the formation of other lymphocytes (Th17, Th1 and CD8+ T lymphocytes) and NK cells[14].

In parallel with these observations, studies in tumor models have shown that the loss of PTPN2 enhances the effectiveness of antitumor immunotherapy through increased IFN-γ-mediated effects on antigen presentation and increased growth suppression of tumor cells. Moreover, PTPN2 deletion results in increased T-cell infiltration and cytotoxicity in chimeric antigen receptor (CAR) T-cell therapy, suggesting that the therapeutic inhibition of PTPN2 may potentiate the effects of immunotherapies that induce an IFN-γ response and toxicity[17]. Therefore, PTPN2 is considered one of the most promising targets for enhancing IFN-γ signaling and the subsequent response to immune checkpoint inhibitor therapy. While PTPN2 exerts these effects primarily through the JAK/STAT signaling pathway in both immune-cold and immune-hot malignancies, the interactions of this protein with the AKT, Src family kinase, and MEK/ERK pathways highlight its extremely complex regulatory network in oncogenesis, tumor behavior and therapy. Indeed, although earlier studies demonstrated a tumor-suppressive role of PTPN2 in many cancers, current data indicate that PTPN2 plays diverse roles in different tumors, which may vary depending on the cancer subtype of even the same organ[18].

In experimental studies, the induction of SFK and STAT3 signaling, as well as tumorigenicity, by the loss of PTPN2 expression has been observed in breast cancer. However, deletion of PTPN2 led to increased STAT-1-dependent T-cell recruitment and PD-L1 expression, resulting in improved efficacy of anti-PD-1 therapy in murine triple-negative breast cancer (TNBC) models. Moreover, PTPN2 expression is correlated with unfavorable outcomes in patients with the luminal A and HER2+ subtypes but does not appear to have predictive potential in TNBC[19]. Similarly, deletion of the PTPN2 gene is a strong indicator of a poor response to tamoxifen treatment and is linked to increased levels of activated Akt in estrogen receptor-positive breast tumors. These findings indicate that PTPN2 has both positive and negative effects on breast cancer[8].

Data indicate that in the brain, PTPN2 contributes to the development or progression of gliomas and glioblastomas. Recently, the association of PTPN2 expression with a poor survival of patients with gliomas and glioblastomas has been documented[20]. In addition, PTPN2 expression is dependent on the grade of some subtypes of gliomas (wild type for isocitrate dehydrogenase and the mesenchymal subtype) and is correlated with the infiltration of immune cells. Because PTPN2 plays a role in tumor progression through the action of inflammatory cytokines (IFN-γ and TNF-α), as well as via oxidative stress, the combination of anti-PD-1 and anti-PTPN2 therapies may serve as an alternative treatment modality for these tumors[21].

The single-nucleotide polymorphisms rs2847297 and rs2847282 in the PTPN2 gene have been described as potential susceptibility loci for the risk of lung cancer in the European population, especially among individuals who have ever smoked and have squamous carcinoma. PTPN2 also plays a role in the behavior of lung cancer, as its expression and related pathways have been found to be related to metastasis[22].

Elevated levels of PTPN2 indicate a negative prognosis for individuals with thyroid cancer, laryngeal cancer, adrenocortical cancer and chromophobe carcinoma of the kidney. However, PTPN2 is a marker of a favorable prognosis for thymoma, skin cancer and ovarian carcinoma, indicating that PTPN2 serves as a double-edged sword with distinct functions across different tumors[18].

PTPN2 IN GI CANCERS

The roles of PTPN2 in GI cancers have been investigated in a limited number of studies (Tables 1 and 2, Figures 1 and 2). A recent study demonstrated increased PTPN2 expression in squamous cell carcinoma of the esophagus, which was related to a poor response to immunotherapy[18]. In gastric adenocarcinoma, PTPN2 is highly expressed in cancer cells and is related to tumor incidence[23].

Figure 2 Plots of gene copy number changes detected in gastrointestinal cancers among 10953 patients included in the The Cancer Genome Atlas PanCancer Atlas Studies investigating protein tyrosine phosphatase nonreceptor 2. A: Esophageal cancer; B: Gastric cancer; C: Colorectal cancer; D: Liver hepatocellular carcinoma; E: Pancreatic adenocarcinoma.

Table 1 Recent findings of the clinicopathological studies in gastrointestinal cancers related to protein tyrosine phosphatase nonreceptor 2.

Ref.	Organ	Expression	Clinicopathologic parameters	Methods	Prognosis	Therapy related findings
Chen et al[29]	Esophagus	High	NS	Oncomine, Ualcan, TCGA data analysis	NS	-
Tang et al[1]	Esophagus	High	-	TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with TMB and higher TIDE scores; Poor response to therapy
Chen et al[29]	Stomach	High	NS	Oncomine,Ualcan, TCGA data analysis	NS	-
Tang et al[1]	Stomach	High	-	TCGA, GTEx, CGGA, GEO,c BioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with TMB, MSI, tumor purity, polyploidy and HRD
Chen et al[29]	Colon	High	NS	Oncomine, Ualcan, TCGA data	NS	-
Tang et al[1]	Colon	High	-	TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with high immune scores; Positive correlation with neoantigems; Negative correlation with tumor purity, polyploidy and HRD
Zhang et al[18]	Pancreas	Down regulated	-	Human tumor tissue, IHC, RT-PCR, IF, WB, CC, AE	Poor prognosis	-
Kuang et al[25]	Pancreas	High	Positive correlation with stage	Human tumor tissue, IHC, RT-PCR, IF, WB, CC, AE	Poor prognosis; Independent prognostic	Positive correlation with high immune scores
Tang et al[1]	Pancreas	High	-	TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	Poor prognosis	Positive correlation with high immune scores; Positive correlation with HRD, TMB, MSI, tumor purity, polyploidy and HRD
Lee et al[27]	Liver (HCC)	Down regulated	Positive correlation with stage	Human tumor tissue	Poor prognosis	-
Tang et al[1]	Liver (HCC)	High	-	TCGA, GTEx, CGGA, GEO, c BioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with high immune scores; Negative correlation with TMB and tumor purity; Positive correlation with HRD and TIDE scores; Poor response to therapy
Tang et al[1]	Liver (CHOL)	High	-	TCGA, GTEx, CGGA, GEO,c BioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	NS
Li et al[10]	Liver (HCC)	High	Positive correlation with preoperative alfa-protein	TCGA data analysis	Poor prognosis Independent prognostic	Higher immune cell infiltration, EMT and angiogenesis; Positive correlation with TGF-β, Notch and Hedgehog signaling pathways upregulation

Ualcan: The University of Alabama at Birmingham Cancer data analysis Portal; TCGA: The Cancer Genome Atlas; GTEX: Genotype tissue expression project; CGGA: Chinese Glioma Genome Atlas; GEO: Gene expression Omnibus database; STRING: Functional protein association networks; TISCH: Tumor Immune Single-cell Hub; TIMER 2.0: Web server for analysis of tumor-infiltrating immune cells; -: Not performed; TMB: Tumor mutation burden; TIDE: Tumor immune disfunction and exclusion; IHC: Immunohistochemistry; RT-PCR; Reverse transcriptase polymerase chain reaction; IF: Immunofluorescence ; WB: Western blotting; CC: Cell culture; AE: Animal experiment; MSI: Microsatellite instability; HRD: Homologous recombination deficiencies; HCC: Hepatocellular carcinoma; CHOL: Cholangiocarcinoma; EMT: Epithelial-to-mesenchymal transition; NS: Not significant.

Table 2 Recent findings of the experimental studies in gastrointestinal cancers related to protein tyrosine phosphatase nonreceptor 2.

Ref.	Organ	Methods	Findings related to PPTN2
Spalinger et al[14]	Colon	CC, IF	PPTN2 dysfunction in T cells drives the secretion of IFN-γ and IL-17. PPTN2 dysfunction promotes IL-18, IL-1β secretion and increased inflammasome assembly. Protects from CRC development
Manguso et al[15]	Colon	AE	Loss of PTPN2 enhances Tim-3+ CD8+ T cell differentiation promoting anti-tumor immunity
Tang et al[1]	Colon	TCGA, GTEx data analysis	Positive correlation with CD8+ cells. Knockdown inhibits proliferation of cancer cells and leads to abundance of PD-L1
Huang et al[26]	Pancreas	CC, WB	Silencing PTPN2 attenuates the proliferation of cancer cells. PTPN2 regulates the level of tyrosine phosphorylation of KRAS. PTPN2 knockdown was consistent with that of knockdown of KRAS
Kuang et al[25]	Pancreas	TCGA, GTEx data analysis	PTPN2 mRNA expression upregulated and related to JAK-STAT pathway. Down-regulation diminishes tumor burden
Zhang et al[18]	Pancreas	Human tumor tissue, IHC, RT-PCR, IF, WB, CC, AE	Knockdown promotes the migration and invasion abilities. PTPN2 inhibited metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in progression
Grohmann et al[28]	HCC	AE	PTPN2 deletion in hepatocytes promoted T cell recruitment. PTPN2 deletion promotes STAT-3 dependent HCC
Tang et al[1]	HCC	TCGA, GTEx data analysis	Terminal differentiation-induced lncRNA preserved STAT3 phosphorylation via direct interacting with PTPN2. The activation of STAT3 downstream target genes and promote HCC cell growth, migration, and infiltration

CC: Cell culture; IF: Immunofluorescence; CRC: Colorectal cancer; AE: Animal experiment; TCGA: The Cancer Genome Atlas; GTEX: Genotype tissue expression project; IHC: Immunohistochemistry; RT-PCR: Reverse transcriptase polymerase chain reaction; IF: Immunofluorescence; WB: Western blotting; MMP-1: Matrix metalloproteinase-1; lncRNA: Long non-coding RNA; HCC: Hepatocellular carcinoma; PTPN2: Protein tyrosine phosphatase nonreceptor 2.

Recent work on various colon cancer models revealed a significant role for PTPN2 in oncogenesis. PTPN2 protein expression and activity are significantly elevated in human colorectal cancer (CRC) tissue, and this elevation is particularly prominent in immune cells. Furthermore, strong correlations between increased PTPN2 gene expression and decreased T-cell activity, impaired T-cell recruitment, and reduced cytotoxicity were observed. These results suggest that PTPN2 targeting is a very promising strategy for increasing T-cell tumor infiltration and tumor-specific cytotoxic activity, as well as for augmenting the therapeutic response in patients with CRC who are resistant to checkpoint inhibitors because of low immunogenicity. Moreover, a correlation between higher levels of PTPN2 and the incidence of CRC was noted[24].

In a recent study, Zhao et al[9] demonstrated a correlation between low PTPN2 expression and an advanced tumor stage in patients with CRC. Decreased PTPN2 expression was shown to be an indicator of a poor prognosis for patients with these tumors. Interestingly, another study reported the contribution of tumor-associated fibroblasts (TAFs) to the function of PTPN2 in the migration of CRC cells. PTPN2 inhibited the metastasis of CRC with TAFs via the JAK/STAT signaling pathway, which indicated that lower PTPN2 expression might cause TAF-expressed fibroblast-specific protein 1 to induce epithelial-to-mesenchymal transition, which is involved in metastasis. Although these findings warrant further investigation, they suggest that PTPN2 may be involved in CRC carcinogenesis by determining tumor behavior and may be a potential therapeutic target[9].

The role of PTPN2 in the development and progression of pancreatic adenocarcinoma (PAC) has also been studied. Bioinformatic analyses revealed that PTPN2 was an important prognostic signature that regulated the progression of this tumor by activating the JAK/STAT signaling pathway. In PAC cell lines, PTPN2 expression is upregulated compared with that in normal pancreatic epithelial cells, and PTPN2 acts as a key regulator that is associated with a poor prognosis. Profound decreases in tumor cell growth, migration, and invasion were induced via PTPN2 knockdown. A series of enrichment analyses were used to investigate PTPN2-binding proteins and PTPN2 expression-correlated genes, and the results revealed that STAT1 and EGFR, which are related to a poor prognosis in PAC, were important regulators of PTPN2. Furthermore, a strong positive correlation between the levels of PTPN2 and immune checkpoints suggests that this protein could be used as a potential target to develop novel therapeutic approaches for PAC[25]. In patients with KRAS-mutant PAC, increased PTPN2 expression is significantly associated with a poor prognosis. In addition, PTPN2 is involved in the activation of KRAS and its downstream signaling via the negative regulation of tyrosine phosphorylation of this protein. Hence, KRAS mutation-bearing tumors are resistant to immune checkpoint blockade, which suggests that PTPN2 may serve as a new therapeutic target[26].

A previous genome-wide study of 32 patients with hepatocellular carcinoma (HCC) demonstrated that PTPN2 was among the downregulated genes, which were correlated with lymph node metastasis. In another study, the deletion of PTPN2 in mouse hepatocytes significantly accelerated chemical carcinogen-induced HCC. Notably, the oxidative environment of this tumor induces PTPN2 inactivation, which in turn induces STAT3 signaling to increase T-cell recruitment. Therefore, STAT3 plays a role in the PTPN2-related pathogenesis of HCC[27]. Similarly, in an experimental study in obese C57BL/6 mice, inactivation of STAT3 signaling and suppression of T-cell recruitment through PTPN2 prevented hepatocyte progression to HCC. In addition, decreased PTPN2 expression was detected in HCC samples compared with that in surrounding healthy liver tissues[28]. On the other hand, Li et al[10] published in the World Journal of Gastrointestinal Oncology, who investigated PTPN2 from multiple biological perspectives, reported that PTPN2 was highly expressed in HCC cells and mediated tumor immune escape by regulating the aggregation of IL-6+, CD3+, CD4+, and CD8+ T cells. This resulted in a significantly worse prognosis for patients in the high PTPN2 expression group than for those in the low PTPN2 expression group. The diversity of data in these few studies does not allow for a common interpretation, and thus, further studies of the role of PTPN2 in the behavior of HCC and its potential in the treatment of this malignancy are needed.

Since the negative regulatory effects of PTPN2 on PD-L1 and its critical role in the immune system have been proven, the use of PTNP2 for detecting the efficacy of immunotherapy has been investigated in recent studies, including studies on GI cancers. A comprehensive analysis demonstrated that PTPN2 levels were positively correlated with the tumor mutation burden, which is highly related to the efficacy of PD-1/PD-L1 inhibitors in colon, stomach and esophageal cancers. On the other hand, negative relationships were observed in cholangiocarcinoma and HCC. Although a strong correlation between PTPN2 expression and neoantigens that are targeted for immunotherapy has been reported in colon cancer, there is an inverse relationship between PTPN2 expression and polyploidy. However, in cancers of the esophagus and stomach, PTPN2 is positively correlated with polyploidy, which is strongly associated with chromosomal instability in these cancers[18,29] (Table 1).

Therefore, these findings emphasize that PTPN2 has heterogeneous effects on different tumors and even on the same type of GI cancer, similar to tumors of other organs. This situation limits the recommendation of PTPN2 as a potential biomarker for predicting cancer prognosis and the efficacy of immunotherapy against GI tumors and necessitates further studies in larger cohorts to better understand the role of this protein in tumor behavior and its effects on treatment[29].

PTPN2 IN ONCOLOGICAL APPLICATIONS

A recent study by Baumgartner et al[17] revealed a novel approach to tumor immunotherapy that uses the small-molecule inhibitor ABBV-CLS-484 (AC484) to target and inhibit the active sites of PTPN2 and PTPN type 1 (PTPN1). This approach has strong potential to induce antitumor immunity. After a structure-based compound design was developed, compound screening identified the small-molecule inhibitor AC484, which works mainly against tumors through the following mechanisms: (1) Increases the sensitivity of tumor cells to IFN-γ; (2) Promotes the activation of human immune cells and improves T-cell function; (3) Involves CD8+ and NK cells in mediating its antitumor effects; (4) Induces proinflammatory remodeling of the TME, contributing to antitumor immunity; (5) Increases the diversity of TCRs in tumors; (6) Promotes the production of specific CD8+ effector T cells; (7) Prevents T-cell exhaustion; and (8) Improves T-cell effector functions and adaptability[17,30].

Two orally available active-site dual PTPN2/PTP1B inhibitors, ABBV-CLS-5 and ABBV-CLS-484, are currently in phase 1 clinical trials for advanced or metastatic tumors (NCT04777994 and NCT04417465). Identifying PTPN2-selective molecules with appropriate pharmacological profiles has proven challenging because of significant similarity between PTPN2 and PTP1B, especially at the catalytic site[31,32]. AbbVie and Calico have developed and tested preclinically dual PTPN2/PTP1B proteolysis-targeting chimera inhibitors that induce the selective degradation of PTPN2 and PTP1B. PTPN2 is subject to allosteric regulation, suggesting a possibility of selective targeting beyond the catalytic domain, which remains unproven[31,33,34].

A previous study indicated that isoliquiritigenin and doxorubicin could achieve synergistic tumor inhibitory effects. The effect was amplified through CRISPR-based gene editing aimed at PTPN2 to begin long-term immunotherapy. PTPN2 depletion was effectively achieved following treatment with M(I + D)PH nanoparticles, leading to the recruitment of intratumoral infiltrating lymphocytes and increases in the levels of proinflammatory cytokines within the tumor tissue[35].

Zhu et al[36] examined the therapeutic potential of small-molecule PTPN2 inhibitors. Ten inhibitors were synthesized via in silico modeling and structure-based design, followed by functional testing both in vitro and in vivo. The inhibitors alone had minimal effects on mouse B16F10 melanoma cells; however, they significantly increased the sensitivity of tumor cells to IFN-γ treatment in vitro and anti-PD-1 treatment in vivo. Under both conditions, cotreatment with a PTPN2 inhibitor resulted in the suppression of B16F10 cell growth and increases in Stat1 phosphorylation and the expression of IFN-γ response genes. Compared with anti-PD-1 treatment alone, cotreatment with a PTPN2 inhibitor in vivo significantly diminished the growth of melanoma and colorectal tumors and increased mouse survival while also promoting increased tumor infiltration by granzyme B+CD8+ T cells. These results were obtained with representative mouse and human colon and lung cancer cell lines. These findings indicate that small-molecule inhibitors of PTPN2 could serve as sensitizing agents for immunotherapy-resistant cancers.

Wiede et al[37] reported that the deletion of PTPN2 in T cells enhanced cancer immunosurveillance and improved the efficacy of adoptively transferred tumor-specific T cells. T-cell-specific deficiency of PTPN2 inhibited tumor formation in aged mice that were heterozygous for the tumor suppressor p53. The adoptive transfer of PTPN2-deficient CD8+ T cells markedly inhibited tumorigenesis in mice with mammary tumors. Additionally, the deletion of PTPN2 in T cells that expressed a CAR targeting the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT5 signaling, resulting in increased activation and homing of CAR-T cells. This promoted the elimination of HER-2+ breast tumors in vivo in the presence of tumors expressing CXCL9/10. These findings identify PTPN2 as a target for improving T-cell-mediated antitumor immunity and CAR-T-cell therapy for solid tumors.

Another study reported a multifunctional nanotherapeutic system that synergized photothermal therapy (PTT) and immunotherapy to improve therapeutic outcomes of melanoma treatment. The researchers selected copper sulfide (CuS) as a semiconductor nanomaterial, which functions as a near-infrared light-triggered photothermal transducer for tumor hyperthermia and acts as a vital carrier for modifying the Cas9 ribonucleoprotein that targets PTPN2 on its surface. PTPN2 depletion was effectively achieved following treatment with CuS-RNP^@PEI nanoparticles, resulting in the accumulation of intratumoral CD8+ T lymphocytes in tumor-bearing mice and the upregulation of IFN-γ and TNF-α expression levels in tumor tissue, thus increasing sensitivity to immunotherapy. This effect also synergistically enhanced antitumor efficacy when combined with PTT-induced tumor ablation and immunogenic cell death[38].

Zheng et al[39] described the design and development of Compound 4, a novel small-molecule PTPN2/N1 inhibitor with nanomolar inhibitory potential, adequate in vivo oral bioavailability, and significant in vivo antitumor activity. A novel programmable unlocking nanomatryoshka-CRISPR system (PUN) has been developed to target PD-L1 and PTPN2, aiming for durable, complete, and highly sensitive immunotherapy[40].

In brief, although these results require further studies, the current findings suggest that PTPN2 may have therapeutic potential.

CONCLUSION

In addition to its roles in inflammatory reactions and immunity, PTPN2 is a protein that significantly impacts cancers through its involvement in oncogenesis, tumor progression, and therapeutic responses. The expression of PTPN2 in GI malignancies and its association with aggressive tumor cell behavior necessitate further investigation in larger cohorts. The relationships between PTPN2 and progression-related clinicopathological parameters, as well as its potential as an independent prognostic factor and indicator of aggressive tumor behavior in patients with GI tumors, necessitate additional investigation. The strong associations between PTPN2 and various pathways, such as the JAK/STAT and MEK/ERK pathways, as well as PD-L1, in GI cancers suggest that this protein could serve as a potential therapeutic target, particularly in treatment-resistant patients.