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

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...

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Published in:	Oncoimmunology Vol. 12; no. 1; p. 2201147
Main Authors:	Blomberg, Olga S., Kos, Kevin, Spagnuolo, Lorenzo, Isaeva, Olga I., Garner, Hannah, Wellenstein, Max D., Bakker, Noor, Duits, Danique E.M., Kersten, Kelly, Klarenbeek, Sjoerd, Hau, Cheei-Sing, Kaldenbach, Daphne, Raeven, Elisabeth A.M., Vrijland, Kim, Kok, Marleen, de Visser, Karin E.
Format:	Journal Article
Language:	English
Published:	United States 31.12.2023
Subjects:	Animals Breast Neoplasms - immunology Breast Neoplasms - therapy CD8-Positive T-Lymphocytes - immunology Humans Immune Checkpoint Inhibitors - therapeutic use Killer Cells, Natural - immunology Lymphocyte Activation Mice Myeloid Cells - immunology Neoadjuvant Therapy Neoplasm Metastasis T-Lymphocytes, Regulatory - immunology regulatory T cells Breast cancer metastasis myeloid cells resistance mechanisms neoadjuvant immune checkpoint blockade
ISSN:	2162-402X, 2162-402X
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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 (T ), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. T 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 in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, T levels were elevated upon ICB. Depletion of T 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 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 extending metastasis-related survival, independent of a primary tumor response.
AbstractList	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 ), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. T 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 in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, T levels were elevated upon ICB. Depletion of T 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 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 extending metastasis-related survival, independent of a primary tumor response.
Author	Kersten, Kelly Spagnuolo, Lorenzo Isaeva, Olga I. Vrijland, Kim Hau, Cheei-Sing Kaldenbach, Daphne Garner, Hannah Kos, Kevin Kok, Marleen Raeven, Elisabeth A.M. Blomberg, Olga S. Klarenbeek, Sjoerd Duits, Danique E.M. Wellenstein, Max D. de Visser, Karin E. Bakker, Noor
Author_xml	– sequence: 1 givenname: Olga S. surname: Blomberg fullname: Blomberg, Olga S. organization: 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 – sequence: 2 givenname: Kevin surname: Kos fullname: Kos, Kevin organization: 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 – sequence: 3 givenname: Lorenzo surname: Spagnuolo fullname: Spagnuolo, Lorenzo organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Oncode Institute, Utrecht, The Netherlands – sequence: 4 givenname: Olga I. surname: Isaeva fullname: Isaeva, Olga I. organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 5 givenname: Hannah surname: Garner fullname: Garner, Hannah organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Oncode Institute, Utrecht, The Netherlands – sequence: 6 givenname: Max D. surname: Wellenstein fullname: Wellenstein, Max D. organization: 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 – sequence: 7 givenname: Noor surname: Bakker fullname: Bakker, Noor organization: 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 – sequence: 8 givenname: Danique E.M. surname: Duits fullname: Duits, Danique E.M. organization: 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 – sequence: 9 givenname: Kelly surname: Kersten fullname: Kersten, Kelly organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 10 givenname: Sjoerd surname: Klarenbeek fullname: Klarenbeek, Sjoerd organization: Experimental Animal Pathology Facility, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 11 givenname: Cheei-Sing surname: Hau fullname: Hau, Cheei-Sing organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Oncode Institute, Utrecht, The Netherlands – sequence: 12 givenname: Daphne surname: Kaldenbach fullname: Kaldenbach, Daphne organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Oncode Institute, Utrecht, The Netherlands – sequence: 13 givenname: Elisabeth A.M. surname: Raeven fullname: Raeven, Elisabeth A.M. organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Oncode Institute, Utrecht, The Netherlands – sequence: 14 givenname: Kim surname: Vrijland fullname: Vrijland, Kim organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Oncode Institute, Utrecht, The Netherlands – sequence: 15 givenname: Marleen surname: Kok fullname: Kok, Marleen organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 16 givenname: Karin E. orcidid: 0000-0002-0293-868X surname: de Visser fullname: de Visser, Karin E. organization: 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
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Keywords	regulatory T cells Breast cancer metastasis myeloid cells resistance mechanisms neoadjuvant immune checkpoint blockade
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Snippet	The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the...
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SubjectTerms	Animals Breast Neoplasms - immunology Breast Neoplasms - therapy CD8-Positive T-Lymphocytes - immunology Humans Immune Checkpoint Inhibitors - therapeutic use Killer Cells, Natural - immunology Lymphocyte Activation Mice Myeloid Cells - immunology Neoadjuvant Therapy Neoplasm Metastasis T-Lymphocytes, Regulatory - immunology
Title	Neoadjuvant immune checkpoint blockade triggers persistent and systemic T reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors
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