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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Systemic inhibition of PTPN22 augments anticancer immunity
Won Jin Ho1, Sarah Croessmann2, Jianping Lin3
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, United States of America.
Abstract:
Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a novel small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8+ T cells and macrophage subpopulations toward MHC-II expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD1-PDL1 axis in the setting of PTPN22 inhibition could be further leveraged with PD1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.
Insights
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) regulates T cell signaling and impacts cancer risk. Inhibiting PTPN22 enhances antitumor immunity, suggesting it as a novel target for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a known regulator of T cell receptor (TCR) signaling in autoimmune diseases.
- The role and therapeutic potential of PTPN22 in cancer immunotherapy remain largely unexplored.
Purpose of the Study:
- To investigate the role of PTPN22 in cancer and its potential as a target for cancer immunotherapy.
- To evaluate the antitumor effects of PTPN22 inhibition.
Main Methods:
- Analysis of a germline PTPN22 variant (rs2476601) in cancer patients.
- Assessment of PTPN22 expression in tumors and its association with immune markers.
- Studies in mouse models lacking PTPN22 to evaluate antitumor immunity.
- Development and testing of a novel small molecule PTPN22 inhibitor (L-1).
- Investigation of immune cell activation (CD8+ T cells, macrophages) and the PD1-PDL1 axis.
Main Results:
- A germline PTPN22 variant (rs2476601) was associated with a reduced likelihood of cancer.
- PTPN22 deficiency in mice enhanced antitumor activity, increasing infiltration and activation of immune cells (macrophages, NK cells, T cells).
- The PTPN22 inhibitor L-1 replicated the antitumor effects of genetic knockout.
- PTPN22 inhibition promoted CD8+ T cell and M1-like macrophage activation.
- Combined PTPN22 and PD1 inhibition, or the presence of the rs2476601 variant, improved responses to immunotherapy.
Conclusions:
- PTPN22 plays a significant role in regulating the immune response to cancer.
- PTPN22 is a druggable target for enhancing cancer immunotherapy.
- Targeting PTPN22 can augment antitumor immunity through modulation of T cells and macrophages, and potentially synergize with checkpoint inhibitors.
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