PTPN1/2 inhibition induces highly functional terminal effector CD8 T cells through autocrine IL-10
Abstract Increased understanding of the modulatory pathways controlling CD8 T cell responses has led to the formulation of successful checkpoint inhibitor-based immunotherapies against cancer. However, their effectiveness is limited to a few tumor types, motivating the search for novel combinatorial strategies. PTPN1 and PTPN2 are two homologous protein tyrosine phosphatases recently proposed as potent intracellular checkpoints. Furthermore, their catalytic domain is a propitious target for small-molecule pharmacological intervention. Herein we investigated the potential effects of conditional genetic deletion of either or both phosphatases in mouse CD8 T cells, one of the main effectors in cancer immunotherapy. Our results demonstrated that hemizygous deletion of PTPN1 in a PTPN2 deficient background heightens the enhanced effector phenotype already observed in PTPN2 defective CD8 T cells. This functional gain is mediated by an autocrine IL-10 positive feedback loop. Pharmacological inhibition with a PTPN1/2 small-molecule inhibitor yielded similar results, highlighting the importance of simultaneously inhibiting both phosphatases. Our study uncovers a novel mechanism by which the downregulation of PTPN1 and PTPN2 act as a powerful tool for potentiating CD8 cytotoxic responses..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 11. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Perez-Quintero, Luis-Alberto [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.04.17.537264 |
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XBI039294897 |
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| 520 | |a Abstract Increased understanding of the modulatory pathways controlling CD8 T cell responses has led to the formulation of successful checkpoint inhibitor-based immunotherapies against cancer. However, their effectiveness is limited to a few tumor types, motivating the search for novel combinatorial strategies. PTPN1 and PTPN2 are two homologous protein tyrosine phosphatases recently proposed as potent intracellular checkpoints. Furthermore, their catalytic domain is a propitious target for small-molecule pharmacological intervention. Herein we investigated the potential effects of conditional genetic deletion of either or both phosphatases in mouse CD8 T cells, one of the main effectors in cancer immunotherapy. Our results demonstrated that hemizygous deletion of PTPN1 in a PTPN2 deficient background heightens the enhanced effector phenotype already observed in PTPN2 defective CD8 T cells. This functional gain is mediated by an autocrine IL-10 positive feedback loop. Pharmacological inhibition with a PTPN1/2 small-molecule inhibitor yielded similar results, highlighting the importance of simultaneously inhibiting both phosphatases. Our study uncovers a novel mechanism by which the downregulation of PTPN1 and PTPN2 act as a powerful tool for potentiating CD8 cytotoxic responses. | ||
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| 700 | 1 | |a Martinez-Cordoba, Zuzet |0 (orcid)0000-0002-3981-6707 |4 aut | |
| 700 | 1 | |a Feng, Chu-Han |0 (orcid)0000-0003-3967-8831 |4 aut | |
| 700 | 1 | |a Aubry, Isabelle |4 aut | |
| 700 | 1 | |a Carli, Cedric |4 aut | |
| 700 | 1 | |a Kamyabiazar, Samaneh |0 (orcid)0000-0003-0170-4133 |4 aut | |
| 700 | 1 | |a Pacis, Alain |0 (orcid)0000-0003-4883-6176 |4 aut | |
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| 700 | 1 | |a Pike, Kelly-Anne |4 aut | |
| 700 | 1 | |a Delisle, Jean-Sebastien |0 (orcid)0000-0003-1460-7287 |4 aut | |
| 700 | 1 | |a Tremblay, Michel L. |0 (orcid)0000-0002-0281-541X |4 aut | |
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