Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy
Background Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combina...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2020-10-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001439.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850194682882031616 |
|---|---|
| author | Jeanne Cheung Rafael Cubas Zia Khan Qian Gong Marina Moskalenko Huizhong Xiong Qinglin Ou Christine Pai Ryan Rodriguez Andrew C Chan |
| author_facet | Jeanne Cheung Rafael Cubas Zia Khan Qian Gong Marina Moskalenko Huizhong Xiong Qinglin Ou Christine Pai Ryan Rodriguez Andrew C Chan |
| author_sort | Jeanne Cheung |
| collection | DOAJ |
| description | Background Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.Results Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.Conclusions Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets. |
| format | Article |
| id | doaj-art-32d03c95b9b246bf87576f6584fcdd1a |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-32d03c95b9b246bf87576f6584fcdd1a2025-08-20T02:13:56ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001439Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapyJeanne Cheung0Rafael Cubas1Zia Khan2Qian Gong3Marina Moskalenko4Huizhong Xiong5Qinglin Ou6Christine Pai7Ryan Rodriguez8Andrew C Chan9Aff1 grid.418158.10000000405344718Genentech, Inc. South San Francisco CA USA1 Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA2 Department of Human Genetics, Genentech, Inc, South San Francisco, California, USA3 Department of Research- Biology, Genentech, Inc, South San Francisco, California, USA1 Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA1 Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA3 Department of Research- Biology, Genentech, Inc, South San Francisco, California, USA3 Department of Research- Biology, Genentech, Inc, South San Francisco, California, USADepartment of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, Illinois, USA3 Department of Research- Biology, Genentech, Inc, South San Francisco, California, USABackground Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.Results Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.Conclusions Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.https://jitc.bmj.com/content/8/2/e001439.full |
| spellingShingle | Jeanne Cheung Rafael Cubas Zia Khan Qian Gong Marina Moskalenko Huizhong Xiong Qinglin Ou Christine Pai Ryan Rodriguez Andrew C Chan Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy |
| title_full | Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy |
| title_fullStr | Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy |
| title_full_unstemmed | Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy |
| title_short | Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy |
| title_sort | autoimmunity linked protein phosphatase ptpn22 as a target for cancer immunotherapy |
| url | https://jitc.bmj.com/content/8/2/e001439.full |
| work_keys_str_mv | AT jeannecheung autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT rafaelcubas autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT ziakhan autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT qiangong autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT marinamoskalenko autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT huizhongxiong autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT qinglinou autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT christinepai autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT ryanrodriguez autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy AT andrewcchan autoimmunitylinkedproteinphosphataseptpn22asatargetforcancerimmunotherapy |