ICIs are considered promising cancer therapeutics that maintain the imbalance between immune surveillance and cancer promotion. Clinical evidence proved that some ICIs, such as anti-PD-1/PD-L1 agents, are superior to conventional chemotherapy [
27]. However, certain types of cancer, such as glioblastomas, are refractory to a monotherapy with ICIs [
27,
28]. The special adverse events caused by ICIs cannot be overlooked either [
29]. These negative results encouraged us to discover other immunotherapeutic targets and treatment strategies to treat cancer.
PTPN2 has recently been identified as a novel immunotherapy target, and deletion of this gene could increase the therapeutic efficacy of PD-1 blockade [
17]. In this study, we characterized PTPN2 mRNA levels in 996 patients with glioma. We observed that PTPN2 transcript levels increased with the glioma grade and were associated with IDH wild-type gliomas and the mesenchymal subtype of GBM. Moreover, our results proved the prognostic value of PTPN2 both for patients with glioma and GBM. These results suggest a crucial role for PTPN2 in the malignant biological process of gliomas.
Next, we conducted a comprehensive analysis of the biological functions associated with PTPN2 in glioma. Similar to the expression of PD-L1, TIM3, and IDO [
10,
11,
30], PTPN2 expression was closely related to the immune and inflammatory responses, as well as a higher invasion of immune cells. PTPN2 is a key negative regulator of the immune and inflammatory responses, and its single nucleotide polymorphism is linked with a high susceptibility to autoimmune diseases [
31]. Moreover, loss of
Ptpn2 resulted in severe systemic inflammation and autoimmunity and increased number of immune cells in mice [
32]. These results indicate that PTPN2 inhibits the immune response and is associated with autoimmunity disease. Moreover, deletion of
ptpn2 increased the sensitivity to T cell immunity in melanoma models, suggesting a novel target for immunotherapy in cancers [
17]. We found a higher infiltration of antitumor immune cells (CD8
+ T cells, TAMs, and NK cells) in gliomas with high PTPN2 expression, which is not in agreement with a previous study that reports a significant increase in the number of CD8α
+ cells in PTPN2-deficient tumors [
17]. These conflicting results need to be clarified in future studies, but it is likely to indicate that PTPN2 does not affect CD8
+ cell infiltration in tumors. We speculate that high PTPN2 expression level is an adaptive mechanism of cancer immunosurveillance, as we found a higher number of infiltrating antitumor immune cells. Moreover, PTPN2 was shown to restrain CD8
+ T cell responses to maintain immune tolerance in mice [
33]. PTPN2 also inhibits T cell development by negatively regulating IL-7R/STAT signaling in T cell progenitors [
34], and the differentiation of macrophages is negatively regulated by
Ptpn2 in mice [
35]. Furthermore, a correlation between PTPN2 transcript levels and immunosuppressive cells, such as neutrophils, MDSCs, and Tregs, was observed, with neutrophils [
36,
37], MDSCs [
38], and Tregs [
39] exhibiting strong immunosuppressive activities and contributing to poor clinical outcomes in patients with cancers. However, future studies are needed to investigate the precise interaction between PTPN2 and immunosuppressive cells. In summary, these results report PTPN2 as a negative prognostic factor in cancer. Consequently, PTPN2 could be a key element in the immunomodulation of immune cells.
The combination of various ICIs has demonstrated clinical benefits in both preclinical studies and clinical trials [
7,
8,
12]. While PTPN2 blockade could be used as a monotherapy target, it could also increase the sensitivity of other ICIs in the treatment of patients with cancer. Sensitivity of the immunotherapy increased by PTPN2 loss is dependent on IFNγ signaling [
17]. Moreover, IFNγ signaling is a crucial pathway in the resistance to anti-PD-1 therapy in patients with cancer [
40,
41]. Thus, it can be inferred that the combination of anti-PD-1 and anti-PTPN2 therapy may be an alternative treatment method. Future research is needed to further explore our hypothesis, as we did not analyze PTPN2 protein levels with regard to clinicopathological factors, inflammatory activities, immune response, and immune cell infiltration. It is known that mRNA expression does not necessarily correlate with protein levels, as the process of transcription can be altered in cancers [
42]. Thus, it will be necessary to study PTPN2 protein levels to confirm the crucial role of PTPN2 in gliomas.