Neoadjuvant immune checkpoint blockade triggers persistent and systemic T reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors
OncoImmunology, vol. 12, pp. 2201147
Abstract
The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (Tregs), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. Tregs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of Tregs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, Treg levels were elevated upon ICB. Depletion of Tregs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of Tregs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of Tregs, extending metastasis-related survival, independent of a primary tumor response.
Authors 16
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Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Leiden University Medical Center
Netherlands Cancer Institute
Oncode Institute
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Leiden University Medical Center
Netherlands Cancer Institute
Oncode Institute
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Netherlands Cancer Institute
Oncode Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Netherlands Cancer Institute
Oncode Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Leiden University Medical Center
Netherlands Cancer Institute
Oncode Institute
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Leiden University Medical Center
Netherlands Cancer Institute
Oncode Institute
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Leiden University Medical Center
Netherlands Cancer Institute
Oncode Institute
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
-
The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute
Experimental Animal Pathology Facility, Netherlands Cancer Institute, Amsterdam, Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Netherlands Cancer Institute
Oncode Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Netherlands Cancer Institute
Oncode Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Netherlands Cancer Institute
Oncode Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Netherlands Cancer Institute
Oncode Institute
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
-
The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
-
Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Leiden University Medical Center
Netherlands Cancer Institute
Oncode Institute
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, Utrecht, The Netherlands
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