PTP Inhibition Improves the Macrophage Antitumor Immune Response and the Efficacy of Chemo- and Radiotherapy

Nestor Prieto-Dominguez; Paran Goel; Oluwagbemiga A. Ojo; Katarina Moretto; Alisha Holtzhausen; Angel Humphryes; Xinyue Zhou; Valeriya Kuznetsova; Francesca Dempsey; Kelly Pittman; Rui Lu; Todd J. Green; Lewis Z. Shi; Robert S. Welner; H. Shelton Earp; Eric Ubil

doi:10.1158/2326-6066.CIR-24-0335

PTP Inhibition Improves the Macrophage Antitumor Immune Response and the Efficacy of Chemo- and Radiotherapy

Nestor Prieto-Dominguez, Paran Goel, Oluwagbemiga A. Ojo, Katarina Moretto, Alisha Holtzhausen, Angel Humphryes, Xinyue Zhou, Valeriya Kuznetsova, Francesca Dempsey, Kelly Pittman, Rui Lu, Todd J. Green, Lewis Z. Shi, Robert S. Welner, H. Shelton Earp, Eric Ubil

Microbiology, Immunology, and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

Abstract

Traditional anticancer therapies induce tumor cell death and subsequent release of damage-associated molecular patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment, macrophages often adopt a pro–wound healing, rather than proinflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll-like receptor signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the proinflammatory response, even in the presence of Pros1. Combining protein tyrosine phosphatase (PTP) inhibition with traditional therapeutics, such as chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40% to 90% reduction in tumor growth in multiple treatment-refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anticancer therapeutic agents.

Original language	English
Pages (from-to)	749-766
Number of pages	18
Journal	Cancer Immunology Research
Volume	13
Issue number	5
DOIs	https://doi.org/10.1158/2326-6066.CIR-24-0335
State	Published - May 2025

Bibliographical note

Publisher Copyright:
©2025 American Association for Cancer Research.

Funding

We gratefully acknowledge Carl Townsend, Ashley Wilson, Nilajah Buchanan, and Tiffany Ricketts for contributions to histological staining and Western blot preparation. We also thank the UAB Flow Cytometry and Single Cell Core Facility, particularly Drs. Shanrun Liu and Mike Crowley, as well as the UAB Comparative Pathology Lab, including Dr. Jeremy Foote and Sherri Coffman, and the UAB Transgenic and Genetically Engineered Models Core. We also thank Dr. Hind Lal for assistance with cell viability assays. We appreciate the contributions from UNC, including those from Charlene Santos and the UNC Animal Studies Core, and UNC Lineberger core facilities, including the Animal Histopathology and Laboratory Medicine Core, Translational Pathology Laboratory, and Histology Core. We gratefully acknowledge Drs. Yuliya Pylayeva-Gupta and Shu-Mang Feng for donations of murine pancreatic and lung cancer cell lines, respectively. This research was supported by the NCI of the NIH under grant numbers RO1-CA205398 (H.S. Earp), RO1-CA279849 (L.Z. Shi), K22-CA237742 (E. Ubil), and RO1-CA262241 (E. Ubil).

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute
UAB Comparative Pathology Lab
Universitat Autònoma de Barcelona
Universidad Nacional de Córdoba
National Institutes of Health (NIH)	RO1-CA205398, RO1-CA279849, K22-CA237742, RO1-CA262241

ASJC Scopus subject areas

Immunology
Cancer Research

UN SDGs

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

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10.1158/2326-6066.CIR-24-0335

Cite this

Prieto-Dominguez, N., Goel, P., Ojo, O. A., Moretto, K., Holtzhausen, A., Humphryes, A., Zhou, X., Kuznetsova, V., Dempsey, F., Pittman, K., Lu, R., Green, T. J., Shi, L. Z., Welner, R. S., Earp, H. S., & Ubil, E. (2025). PTP Inhibition Improves the Macrophage Antitumor Immune Response and the Efficacy of Chemo- and Radiotherapy. Cancer Immunology Research, 13(5), 749-766. https://doi.org/10.1158/2326-6066.CIR-24-0335

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abstract = "Traditional anticancer therapies induce tumor cell death and subsequent release of damage-associated molecular patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment, macrophages often adopt a pro–wound healing, rather than proinflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll-like receptor signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the proinflammatory response, even in the presence of Pros1. Combining protein tyrosine phosphatase (PTP) inhibition with traditional therapeutics, such as chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40\% to 90\% reduction in tumor growth in multiple treatment-refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anticancer therapeutic agents.",

author = "Nestor Prieto-Dominguez and Paran Goel and Ojo, \{Oluwagbemiga A.\} and Katarina Moretto and Alisha Holtzhausen and Angel Humphryes and Xinyue Zhou and Valeriya Kuznetsova and Francesca Dempsey and Kelly Pittman and Rui Lu and Green, \{Todd J.\} and Shi, \{Lewis Z.\} and Welner, \{Robert S.\} and Earp, \{H. Shelton\} and Eric Ubil",

note = "Publisher Copyright: {\textcopyright}2025 American Association for Cancer Research.",

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doi = "10.1158/2326-6066.CIR-24-0335",

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Prieto-Dominguez, N, Goel, P, Ojo, OA, Moretto, K, Holtzhausen, A, Humphryes, A, Zhou, X, Kuznetsova, V, Dempsey, F, Pittman, K, Lu, R, Green, TJ, Shi, LZ, Welner, RS, Earp, HS & Ubil, E 2025, 'PTP Inhibition Improves the Macrophage Antitumor Immune Response and the Efficacy of Chemo- and Radiotherapy', Cancer Immunology Research, vol. 13, no. 5, pp. 749-766. https://doi.org/10.1158/2326-6066.CIR-24-0335

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AU - Goel, Paran

AU - Ojo, Oluwagbemiga A.

AU - Moretto, Katarina

AU - Holtzhausen, Alisha

AU - Humphryes, Angel

AU - Zhou, Xinyue

AU - Kuznetsova, Valeriya

AU - Dempsey, Francesca

AU - Pittman, Kelly

AU - Lu, Rui

AU - Green, Todd J.

AU - Shi, Lewis Z.

AU - Welner, Robert S.

AU - Earp, H. Shelton

AU - Ubil, Eric

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N2 - Traditional anticancer therapies induce tumor cell death and subsequent release of damage-associated molecular patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment, macrophages often adopt a pro–wound healing, rather than proinflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll-like receptor signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the proinflammatory response, even in the presence of Pros1. Combining protein tyrosine phosphatase (PTP) inhibition with traditional therapeutics, such as chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40% to 90% reduction in tumor growth in multiple treatment-refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anticancer therapeutic agents.

AB - Traditional anticancer therapies induce tumor cell death and subsequent release of damage-associated molecular patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment, macrophages often adopt a pro–wound healing, rather than proinflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll-like receptor signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the proinflammatory response, even in the presence of Pros1. Combining protein tyrosine phosphatase (PTP) inhibition with traditional therapeutics, such as chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40% to 90% reduction in tumor growth in multiple treatment-refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anticancer therapeutic agents.

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PTP Inhibition Improves the Macrophage Antitumor Immune Response and the Efficacy of Chemo- and Radiotherapy

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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