Neoadjuvant immune checkpoint blockade triggers persistent and systemic T reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors.

Autor:	Blomberg OS; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Kos K; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Spagnuolo L; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Isaeva OI; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Garner H; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Wellenstein MD; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Bakker N; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Duits DEM; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Kersten K; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Klarenbeek S; Experimental Animal Pathology Facility, Netherlands Cancer Institute, Amsterdam, Netherlands., Hau CS; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Kaldenbach D; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Raeven EAM; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Vrijland K; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Kok M; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands., de Visser KE; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2023 Apr 13; Vol. 12 (1), pp. 2201147. Date of Electronic Publication: 2023 Apr 13 (Print Publication: 2023).
DOI:	10.1080/2162402X.2023.2201147
Abstrakt:	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 (T regs ), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. T regs 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 T regs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, T reg levels were elevated upon ICB. Depletion of T regs 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 T regs 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 T regs, extending metastasis-related survival, independent of a primary tumor response. Competing Interests: K.E.d.V. reports research funding from Roche and is consultant for Macomics, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche/Genentech, AZ and an advisory role for BMS, Roche, MSD and Daiichi Sankyo, outside the submitted work. (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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