PTPN2 deletion in T cells promotes anti-tumour immunity and CAR T cell efficacy in solid tumours

Wiede, Florian; Lu, Kun-Hui; Du, Xin; Liang, Shuwei; Hochheiser, Katharina; Dodd, Garron T.; Goh, Pei Kee; Kearney, Conor J.; Meyran, Déborah; Beavis, Paul A.; Henderson, Melissa A.; Park, Simone L.; Waithman, Jason; Zhang, Sheng; Zhang, Zhong-Yin; Oliaro, Jane; Gebhardt, Thomas; Darcy, Phillip K.; Tiganis, Tony

doi:10.1101/757419

Cited by 27 publications

(50 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These phenotypes have been attributed to the important role of PTPN2 in regulating activation of Janus kinases ( 40 ); signal transducers and regulators of transcription-1 (STAT1), STAT3, and STAT5 ( 41 ); as well as T cell receptor (TCR) signaling ( 38 ). Consistent with the key role of PTPN2 loss of function in autoimmunity, recent studies have also validated PTPN2 as an important target for cancer immunotherapy ( 42 , 43 ).…”

Section: Introductionmentioning

confidence: 56%

PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

Hsieh¹,

Svensson²,

Zoccheddu³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 ( PTPN2 ) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2 -haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3 – IL-17 + arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2 . Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15 + Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15 + exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.

show abstract

Section: Introductionmentioning

confidence: 56%

PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

Hsieh¹,

Svensson²,

Zoccheddu³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

show abstract

“…(21)(22)(23)(24). Recent researches demonstrated that PTPN2 deletion can enhance the effectiveness of anti-tumor immunity (8,25,26). Thus, PTPN2 expression is likely to possess potential medical significance in STAD and could be exploited as an attractive immunotherapy target.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the expression of PTPN6 with the loss of pSTAT3 expression could be chosen as a biomarker for the prognosis of peripheral-T cell lymphoma (7). One research published recently noted that a deficiency of PTPN2 could enhance antitumor immunity and the therapeutic efficacy of CAR T cells to solid cancers (8). PTPN22 plays an important part in regulating autophagy and NLR family pyrin domain containing 3 inflammasome activation (9).…”

Section: Introductionmentioning

confidence: 99%

The expression patterns and the prognostic roles of PTPN family members in digestive tract cancers

Chen

Yuan

Jing

2020

Preprint

View full text Add to dashboard Cite

Background Non-receptor protein tyrosine phosphatases (PTPNs) are a set of enzymes involved in the tyrosyl phosphorylation. The present study intended to clarify the associations between the expression patterns of PTPN family members and the prognosis of digestive tract cancers. Method Expression profiling of PTPN family genes in digestive tract cancers were analyzed through ONCOMINE and UALCAN. Gene ontology enrichment analysis was conducted using the DAVID database. The gene–gene interaction network was performed by GeneMANIA and the protein–protein interaction (PPI) network was built using STRING portal couple with Cytoscape. Data from The Cancer Genome Atlas (TCGA) were downloaded for validation and to explore the relationship of the PTPN expression with clinicopathological parameters and survival of digestive tract cancers. Results Most PTPN family members were associated with digestive tract cancers according to Oncomine, Ualcan and TCGA data. For esophageal carcinoma (ESCA), expression of PTPN1, PTPN4 and PTPN12 were upregulated; expression of PTPN20 was associated with poor prognosis. For stomach adenocarcinoma (STAD), expression of PTPN2, PTPN12 and PTPN22 was upregulated in cancer tissue; pathological grade was significantly correlated with PTPN3, PTPN5, PTPN7, PTPN11, PTPN13, PTPN14, PTPN18 and PTPN23; PTPN20 expression was related with both TNM stage and N stage; PTPN22 was associated with T stage and pathological grade; decreased expression of PTPN5 and PTPN13 was associated with worse overall survival of STAD, while elevated PTPN6 expression indicated better prognosis. For colon adenocarcinoma (COAD), expression of PTPN1, PTPN11, PTPN12 and PTPN13 was upregulated, while expression of PTPN18, PTPN21 and PTPN22 was decreased; expression of PTPN5, PTPN12, and PTPN14 was correlated with TNM stage and N stage; high PTPN5 or PTPN7 expression were associated with increased hazards of death. For rectum adenocarcinoma (READ), expression of PTPN12 was upregulated while PTPN21 and PTPN22 were downregulated. Conclusion Members of PTPN family were differently expressed in digestive tract cancers and matched normal tissues. Correlation were found between PTPN genes and clinicopathological parameters of patients. Expression of PTPN12 was upregulated in all of the ESCA, STAD, COAD and READ. PTPN5 was associated with the clinical features and prognosis of both STAD and COAD.

show abstract

“…Protein tyrosine phosphatase non-receptor type 2 (PTPN2) has recently been suggested as a possible target for tumor therapy (11)(12)(13). PTPN2 is a ubiquitously expressed anti-inflammatory protein known to regulate pro-inflammatory signaling pathways by direct dephosphorylation, including several Janus kinases, signal transducer and activator of transcription (STAT) family members and others (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that loss of PTPN2 in myeloid cells and intestinal epithelial cells reduce tumor load and promote immune responses against tumors in a model of colitis-associated colon cancer by increasing IL-1 production and elevating immunogenicity of the tumor (19). Tumor cell-specific and T-cell-specific PTPN2 deletion has been reported to reduce tumor load in subcutaneous tumor models using melanoma and CRC cell lines as well as in mammary tumor models (11)(12)(13). In humans, reduced PTPN2 expression correlated with better treatment response in Tcell acute lymphoblastic leukemia in children (20).…”

Section: Introductionmentioning

confidence: 99%

Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development

Katkeviciutė¹,

Hering²,

Montalban-Arques³

et al. 2021

Journal of Clinical Investigation

View full text Add to dashboard Cite

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC) as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. Particularly, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T-cells and increased PTPN2 levels negatively correlated with PD1, CTLA4, STAT1 and granzyme A. In vivo, T-cell and dendritic cell-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T-cells, as well as CD8+ T-cell infiltration and cytotoxicity into the tumor. In direct relevance to CRC treatment, T-cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced anti-tumor memory formation upon tumor re-challenge in vivo. Our data suggest a role for PTPN2 in suppressing anti-tumor immunity and promoting tumor development in CRC patients. Our in vivo results uncover PTPN2 as a key player in controlling immunogenicity of CRC, with the strong potential to be exploited to promote cancer immunotherapy.

show abstract

PTPN2 deletion in T cells promotes anti-tumour immunity and CAR T cell efficacy in solid tumours

Cited by 27 publications

References 82 publications

PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

The expression patterns and the prognostic roles of PTPN family members in digestive tract cancers

Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development

Contact Info

Product

Resources

About