PTPN2/PTPN1 inhibition enhances ex vivo T- cell responses and potentiates mosunetuzumab activity in chronic lymphocytic leukemia
- 1Department of Hematology, Tel Aviv Sourasky University Medical Center (Ichilov)
- 2Gray Faculty of Medicine and Health Sciences, Tel Aviv University
Abstract
Background: Chronic lymphocytic leukemia (CLL) is characterized by T-cell dysfunction that limits the efficacy of immunotherapies, including CD20×CD3 bispecific antibodies. Protein tyrosine phosphatases non-receptor type 2/1 PTPN2/PTPN1 are central intracellular negative regulators of T-cell activation. Preclinical studies show that deletion or PTPN2/PTPN1 inhibition increased T-cell activation, proliferation, and antitumor activity. This study aimed to investigate the potential of PTPN2/PTPN1 inhibition in combination with the bispecific antibody mosunetuzumab as a therapeutic approach for CLL.
Methods: Peripheral blood mononuclear cells (PBMCs) obtained from CLL patients were used in all experiments. The effects of PTPN2/PTPN1 inhibition in combination with mosunetuzumab, were evaluated using flow cytometry, confocal microscopy, ELISA, and Incucyte Live-Cell Analysis to assess T-cell activation, immune synapse formation and cytotoxic activity.
Results: Pretreatment with the PTPN2/PTPN1 inhibitor ABBV-CLS-484 (AC484) enhanced T-cell activation following CD3/CD28 stimulation, as demonstrated by increased expression of the activation markers CD69 and CD25. Confocal microscopy revealed increased CD8+ T-cell size, enhanced granzyme B expression and release, and more robust immune synapse formation following treatment with mosunetuzumab +/-AC484. Incucyte imaging of CLL-T-cell co-cultures demonstrated enhanced T-cell proliferation, increased CLL-T-cell clustering, and a modest increase in cytotoxicity with the combination of AC484 and mosunetuzumab. Consistent with these findings, ELISA assays showed increased secretion of granzyme B and IFN-γ.
Conclusion: Combining the PTPN2/PTPN1 inhibitor AC484 with mosunetuzumab enhanced T-cell activation, proliferation, granzyme B and IFN-γ secretion, and anti-CLL cytotoxicity in CLL samples, supporting further evaluation of PTPN2/PTPN1 inhibition as a strategy to enhance the efficacy of CLL immunotherapy.
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BibTeX
@article{yitzhak2026ptpn2ptpn1,
title = {{PTPN2/PTPN1 inhibition enhances ex vivo T- cell responses and potentiates mosunetuzumab activity in chronic lymphocytic leukemia}},
author = {Liron Yitzhak and Yamit Shorer Arbel and Yotam Bronstein and Ben-Zion Katz and Yair Herishanu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1948967},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1948967/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PTPN2/PTPN1 inhibition enhances ex vivo T- cell responses and potentiates mosunetuzumab activity in chronic lymphocytic leukemia
AU - Liron Yitzhak
AU - Yamit Shorer Arbel
AU - Yotam Bronstein
AU - Ben-Zion Katz
AU - Yair Herishanu
PY - 2026
DA - 2026/10/08
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1948967
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1948967/full
AB - Background: Chronic lymphocytic leukemia (CLL) is characterized by T-cell dysfunction that limits the efficacy of immunotherapies, including CD20×CD3 bispecific antibodies. Protein tyrosine phosphatases non-receptor type 2/1 PTPN2/PTPN1 are central intracellular negative regulators of T-cell activation. Preclinical studies show that deletion or PTPN2/PTPN1 inhibition increased T-cell activation, proliferation, and antitumor activity. This study aimed to investigate the potential of PTPN2/PTPN1 inhibition in combination with the bispecific antibody mosunetuzumab as a therapeutic approach for CLL. Methods: Peripheral blood mononuclear cells (PBMCs) obtained from CLL patients were used in all experiments. The effects of PTPN2/PTPN1 inhibition in combination with mosunetuzumab, were evaluated using flow cytometry, confocal microscopy, ELISA, and Incucyte Live-Cell Analysis to assess T-cell activation, immune synapse formation and cytotoxic activity. Results: Pretreatment with the PTPN2/PTPN1 inhibitor ABBV-CLS-484 (AC484) enhanced T-cell activation following CD3/CD28 stimulation, as demonstrated by increased expression of the activation markers CD69 and CD25. Confocal microscopy revealed increased CD8+ T-cell size, enhanced granzyme B expression and release, and more robust immune synapse formation following treatment with mosunetuzumab +/-AC484. Incucyte imaging of CLL-T-cell co-cultures demonstrated enhanced T-cell proliferation, increased CLL-T-cell clustering, and a modest increase in cytotoxicity with the combination of AC484 and mosunetuzumab. Consistent with these findings, ELISA assays showed increased secretion of granzyme B and IFN-γ. Conclusion: Combining the PTPN2/PTPN1 inhibitor AC484 with mosunetuzumab enhanced T-cell activation, proliferation, granzyme B and IFN-γ secretion, and anti-CLL cytotoxicity in CLL samples, supporting further evaluation of PTPN2/PTPN1 inhibition as a strategy to enhance the efficacy of CLL immunotherapy.
SN - 1664-3224
ER -