Abstract A018: Targeting PTPN1/PTPN2 with KQ-791 enhances NK cell cytotoxicity during tumor rechallenge
Notice bibliographique
Résumé
Abstract Introduction and Hypothesis: Natural killer (NK) cells are cytolytic innate lymphocytes that play a key role in immune surveillance and elimination of malignant cells, particularly those that evade T cell responses and contribute to metastasis. NK cells eliminate tumor cells through multiple cytotoxic mechanisms, including direct release of cytotoxic granules to induce tumor cells apoptosis. Their ability to recognize and kill tumor cells without prior antigen presentation makes them attractive candidates for allogeneic cell-based cancer immunotherapy. However, the lack of persistent cytotoxic activity in cancer patients remains challenging to improve NK cell-based immunotherapy. Protein tyrosine phosphatases PTPN1 (PTP1B) and PTPN2 (TC-PTP) are negative regulators of cytokine signaling and immune cell activation. In our previous studies, we showed that pharmacological dual-inhibition of PTPN1/PTPN2 enhanced expression of cytokine-mediated cytotoxic granules in NK cells. Since NK cell mediated serial killing involves persistent release of cytolytic granules, we hypothesize that dual inhibition of PTPN1 and PTPN2 will enhance NK cell-mediated persistent cytotoxicity during tumor rechallenges. Experimental Methods: We used a competitive small molecule inhibitor, KQ-791, targeting PTPN1/PTPN2 in NK cells. To assess the effect of KQ-791 on NK cell cytotoxicity over repeated tumor encounters, we used the Incucyte Live-Cell Analysis System. NK-92 cells were pre-treated for with KQ-791 or PBS, prior to co-culture. GFP expressing U87 tumor cells and NK-92 NK cells were then assayed in co-culture at various effector: target cell ratios. To model tumor rechallenge, fresh U87-GFP cells were added every 2–3 days for five total challenges. IL-2 was replenished at each rechallenge. In one experimental arm, KQ-791 (or PBS) was added again at alternate rechallenges. Tumor cell burden was assessed by measuring integrated fluorescence intensity of GFP+ U87 cells. Images were acquired periodically and analyzed to quantify tumor cell killing. Results: NK cells pre-treated with KQ-791 showed enhanced tumor clearance across all the effector: target ratios at the initial tumor challenge as well as for four subsequent tumor rechallenges. The difference in tumor killing was most evident for the 1:1 effector: target cell ratio. Retreatment with KQ-791 enhanced killing at tumor rechallenge. Conclusion: These findings demonstrate that pharmacological inhibition of PTPN1 and PTPN2 using KQ-791 enhances NK-92–mediated persistent tumor cell killing during repeated tumor challenges. The observed effect was particularly pronounced at lower effector-to-target ratios, highlighting the potential of KQ-791 to improve NK cell persistence and efficacy under limiting conditions. This study provides evidence supporting the use of PTPN1/2 inhibitors to potentiate NK cell–based immunotherapy, warranting further investigation in primary NK cells and in vivo models. Citation Format: Sonali Uttam, Chu-Han Feng, Isabelle Aubry, David Langlais, Pierre Laneuville, Michel L. Tremblay. Targeting PTPN1/PTPN2 with KQ-791 enhances NK cell cytotoxicity during tumor rechallenge [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr A018.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,002 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».