A review.Targeting protein tyrosine kinase (PTK) signaling pathways to suppress tumor growth, survival and chemotherapeutic resistance has been a mainstay of cancer therapy for decades.The early success of imatinib targeting the oncogenic BCR-ABL1 fusion protein, a causative transforming event in chronic myeloid leukemia, spearheaded the investment of significant resources that has led to the development of PTK inhibitors approved for the treatment of both solid and hematol. malignancies.1.By contrast, the targeting of protein tyrosine phosphatases (PTPs) has only recently garnered the attention of cancer researchers, with the focus being on PTPs such as SHP-2 and PTP1B that are overexpressed in cancer and promote tumor growth and metastases.2, 3, 4.In general, most PTPs serve to attenuate oncogenic PTK signaling and function as tumor suppressors, with several PTPs being deleted or inactivated in human cancer.This includes the tyrosine-specific phosphatase PTPN2 (also known as TCPTP) that dephosphorylates and inactivates EGFR, SRC family kinases, Janus-activated kinases (JAKs)-1 and -3, and signal transducer and activators of transcription (STATs)-1, -3 and -5 in a cell type and context-dependent manner.5, 6, 7PTPN2 is deleted in 6% of all T cell acute lymphoblastic leukemias and is associated with constitutive JAK1/STAT5 signaling and tumorigenesis.8 PTPN2 protein is also decreased in estrogen receptor-neg. and triple-neg. breast cancers and promotes SRC and STAT3 signaling and tumorigenicity.7 Other studies have shown that PTPN2 deletion in keratinocytes can exacerbate chem. induced skin carcinogenesis in mice,9 whereas gene expression studies in humans have shown that decreased PTPN2 expression may be associated with liver cancer metastases.10 Indeed given PTPN2's ability to dephosphorylate oncogenic PTKs and their target substrates, including STAT3,5, 7 one might expect that PTPN2 deletion might contribute to the development of a wide variety of human malignancies.Despite this, a recent study from Manguso et al.11 in Nature has suggested that PTPN2 deletion may rather be beneficial by mobilizing effective anti-tumor host immunity and increasing susceptibility to immunotherapy.Therefore, although seemingly counterintuitive, inhibiting a bona fide tumor suppressor may be favorable in the context of established disease.Cancer development is heavily influenced by the immune response and the ability of tumors to manipulate processes that normally serve to maintain self-tolerance and prevent collateral tissue damage and autoimmunity during anti-microbial immunity.12, 13 Tumor cells are able to suppress the anti-tumor effects of T cells, by among other things expressing ligands for T cell inhibitory receptors such as PD-1 (Programmed Death-1).12, 13 Mols. such as PD-1 are upregulated on activated T cells and function as immune checkpoints to control the magnitude of the immune response.12, 13 The intracellular domain of PD-1 interacts with the tyrosine phosphatases SHP-1 and SHP-214 that inhibit the PTK LCK and thereby T cell receptor signaling.14 This normally serves to suppress T cell responses to cognate peptide-MHC and the development of overt autoreactivity.Tumors hijack this process by upregulating on their cell surface ligands for T cell inhibitory receptors, including PD-1 ligand (PD-L1).12, 13.The engagement of PD-1 on T cells by PD-L1 on tumor cells suppresses T cell receptor signaling and anti-tumor immunity and promotes T cell exhaustion.Therapeutic antibodies targeting the PD-1/PD-L1 pathway, as well as other immune checkpoints, such as CTLA4, have been remarkably successful in treating varied human cancers, including melanoma, where durable responses are seen in 20% of patients treated with anti-CTLA4.15.Tumor cells increase PD-L1 in response to cytokines, in particular interferon-γ (IFN-γ) produced by intratumoral CD8+ T cells and NK cells.13.IFN-γ promotes JAK1/2-mediated STAT1 Y701 phosphorylation and the translocation of STAT1 to the nucleus to transcribe varied immunity-related genes, including PD-L1.13, 16.PTPN2 is a key neg. regulator of IFN-γ signaling dephosphorylating and inactivating both Y1022/Y1023-phosphorylated JAK1 and Y701-phosphorylated STAT1 (Figure 1).5.Manguso et al.11 demonstrate that PTPN2's ability to suppress IFN-γ signaling in tumor cells has a dramatic effect on the response to immunotherapy.Using CRISPR-Cas9-mediated genome editing they show that Ptpn2 deletion in murine tumor cells renders the corresponding tumors in wild type mice highly susceptible to immune checkpoint blockade with anti-PD-1.11.The enhanced anti-PD-1 response was accompanied by the recruitment of cytotoxic CD8+ T cells, increased antigen presentation, as reflected by the increased expression of MHC-I on tumor cells, and the increased activation of recruited T cells (Figure 1).11.PTPN2-deficient tumor cells expressed higher levels of IFN-γ/STAT1 target genes, including those encoding the T cell chemoattractants CXCL9, CXCL10, CXCL11 and CCL5, and components of the antigen-processing and presentation pathway (Figure 1).11.Notably the increased anti-PD-1 response in vivo could be attributed entirely to the promotion of IFN-γ-induced STAT1 signaling, as the beneficial effects of Ptpn2 deletion were lost when Stat1, Jak1, Ifngr1 or Ifnar2 were also deleted.11.The study did not report on changes in PD-L1 expression, nor in other T cell inhibitory receptor ligands in tumor cells,11 as might be expected from the promotion of IFN-γ/STAT1 signaling.16.The extent to which the increased sensitivity to anti-PD-1 immunotherapy in PTPN2-deficient tumors may have been ascribed to the increased T cell recruitment alone and/or PD-L1 expression requires further investigation.Similarly, it remains to be seen if PTPN2 deletion also sensitizes tumors to other checkpoint inhibitors.A key limitation for immunotherapy is that not all tumors have a high mutation burden and are therefore not immunogenic; such tumors have few tumor-infiltrating lymphocytes and as a consequence remain relatively unresponsive to checkpoint inhibitors.12.The presence of tumor-infiltrating lymphocytes and in particular CD8+ T cells is generally associated with better prognosis and improved response to chemotherapy in cancer.12.For example, in triple-neg. breast cancer the presence of tumor-infiltrating lymphocytes is associated with better prognosis and an increased chance of pathol. complete response to chemotherapy.12.The studies by Manguso et al.11 suggest that PTPN2 inhibition in tumors might provide a means by which to increase the recruitment and activation of tumor-infiltrating lymphocytes and render otherwise non-immunogenic tumors amenable to both chemotherapy and immune checkpoint blockade.Is the inhibition of PTPN2 in cancer sensible.A concern is that PTPN2 inhibition could also promote PTK pathways that drive tumorigenicity that may ultimately promote resistance and overcome the initial benefits of anti-PD-1/PD-L1 immunotherapy.The activation of such oncogenic PTK pathways, was not examined in the PTPN2-deleted tumor cell lines utilized by Manguso et al.11.Moreover, in a subset of patients, immune checkpoint blockade can lead to adverse immune-related toxicities, including for example colitis, vitiligo and in rarer cases, hepatitis, nephritis and type 1 diabetes.PTPN2 SNPs that result in ∼40% reduction in PTPN2 message in T cells have been associated with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease.17, 18.Therefore, the inhibition of PTPN2 in the immune compartment might exacerbate any autoreactivity seen in patients subjected to immune checkpoint blockade.Indeed, homozygous PTPN2 deletion in the hematopoietic compartment in otherwise non-autoimmune-prone C57BL/6 adult mice can promote systemic inflammation and autoimmunity.19.It remains to be determined if PTPN2 partial inhibition, as commonly occurs with drugs, would elicit similar immune complications, or whether a therapeutic window may exist for selectively targeting tumor cells.The findings of Manguso et al.11 redefine our understanding of the role of phosphatases in tumor biol. and more generally, the role of tumor suppressors.Further studies are required to determine if PTPN2 tumor status similarly influences host immunity and tumor growth in humans and whether PTPN2 levels in human tumors may help predict the response to immune checkpoint blockade.It is also important to explore the role of other PTPs involved in the inhibition of JAK/STAT signaling including SHP-1 and SHP-2 that mediate PD-1 action,14 and PTP1B that dephosphorylates JAK2 and Tyk2.5 Importantly, the findings of Manguso et al.11 coincide with important advancements in the PTP field that have allowed for the development of highly specific allosteric PTP inhibitors2, 4 and may herald a new era in cancer drug development focused on inhibiting PTPs to bolster anti-tumor immunity and overcome resistance to immunotherapy.
