PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies

Raghavendra Basavaraja; Hongru Zhang; Ágnes Holczbauer; Zhen Lu; Enrico Radaelli; Charles Antoine Assenmacher; Subin S. George; Vamshidhar C. Nallamala; Daniel P. Beiting; Mirella L. Meyer-Ficca; Ralph G. Meyer; Wei Guo; Yi Fan; Andrew J. Modzelewski; Vladimir S. Spiegelman; Michael S. Cohen; Serge Y. Fuchs

doi:10.1016/j.xcrm.2024.101649

PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies

Raghavendra Basavaraja, Hongru Zhang, Ágnes Holczbauer, Zhen Lu, Enrico Radaelli, Charles Antoine Assenmacher, Subin S. George, Vamshidhar C. Nallamala, Daniel P. Beiting, Mirella L. Meyer-Ficca, Ralph G. Meyer, Wei Guo, Yi Fan, Andrew J. Modzelewski, Vladimir S. Spiegelman, Michael S. Cohen, Serge Y. Fuchs

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Abstract

Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

Original language	English (US)
Article number	101649
Journal	Cell Reports Medicine
Volume	5
Issue number	7
DOIs	https://doi.org/10.1016/j.xcrm.2024.101649
State	Published - Jul 16 2024

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.xcrm.2024.101649

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Basavaraja, R., Zhang, H., Holczbauer, Á., Lu, Z., Radaelli, E., Assenmacher, C. A., George, S. S., Nallamala, V. C., Beiting, D. P., Meyer-Ficca, M. L., Meyer, R. G., Guo, W., Fan, Y., Modzelewski, A. J., Spiegelman, V. S., Cohen, M. S., & Fuchs, S. Y. (2024). PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies. Cell Reports Medicine, 5(7), Article 101649. https://doi.org/10.1016/j.xcrm.2024.101649

@article{ecd3d65b47784bce8e8b41919bddeed1,

title = "PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies",

abstract = "Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.",

author = "Raghavendra Basavaraja and Hongru Zhang and {\'A}gnes Holczbauer and Zhen Lu and Enrico Radaelli and Assenmacher, {Charles Antoine} and George, {Subin S.} and Nallamala, {Vamshidhar C.} and Beiting, {Daniel P.} and Meyer-Ficca, {Mirella L.} and Meyer, {Ralph G.} and Wei Guo and Yi Fan and Modzelewski, {Andrew J.} and Spiegelman, {Vladimir S.} and Cohen, {Michael S.} and Fuchs, {Serge Y.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jul,

day = "16",

doi = "10.1016/j.xcrm.2024.101649",

language = "English (US)",

volume = "5",

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Basavaraja, R, Zhang, H, Holczbauer, Á, Lu, Z, Radaelli, E, Assenmacher, CA, George, SS, Nallamala, VC, Beiting, DP, Meyer-Ficca, ML, Meyer, RG, Guo, W, Fan, Y, Modzelewski, AJ, Spiegelman, VS, Cohen, MS & Fuchs, SY 2024, 'PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies', Cell Reports Medicine, vol. 5, no. 7, 101649. https://doi.org/10.1016/j.xcrm.2024.101649

TY - JOUR

T1 - PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies

AU - Basavaraja, Raghavendra

AU - Zhang, Hongru

AU - Holczbauer, Ágnes

AU - Lu, Zhen

AU - Radaelli, Enrico

AU - Assenmacher, Charles Antoine

AU - George, Subin S.

AU - Nallamala, Vamshidhar C.

AU - Beiting, Daniel P.

AU - Meyer-Ficca, Mirella L.

AU - Meyer, Ralph G.

AU - Guo, Wei

AU - Fan, Yi

AU - Modzelewski, Andrew J.

AU - Spiegelman, Vladimir S.

AU - Cohen, Michael S.

AU - Fuchs, Serge Y.

PY - 2024/7/16

Y1 - 2024/7/16

N2 - Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

AB - Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

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DO - 10.1016/j.xcrm.2024.101649

M3 - Article

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AN - SCOPUS:85198311290

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 7

M1 - 101649

ER -

PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies

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