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They L, Michaud HA, Becquart O, et al. PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody. Oncoimmunology. 2017;6(10):e1353857doi: 10.1080/2162402X.2017.1353857.
They, L., Michaud, H. A., Becquart, O., Lafont, V., Guillot, B., Boissière-Michot, F., Jarlier, M., Mollevi, C., Eliaou, J. F., Bonnefoy, N., & Gros, L. (2017). PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody. Oncoimmunology, 6(10), e1353857. https://doi.org/10.1080/2162402X.2017.1353857
They, Laetitia, et al. "PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody." Oncoimmunology vol. 6,10 (2017): e1353857. doi: https://doi.org/10.1080/2162402X.2017.1353857
They L, Michaud HA, Becquart O, Lafont V, Guillot B, Boissière-Michot F, Jarlier M, Mollevi C, Eliaou JF, Bonnefoy N, Gros L. PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody. Oncoimmunology. 2017 Jul 20;6(10):e1353857. doi: 10.1080/2162402X.2017.1353857. eCollection 2017. PMID: 29123966; PMCID: PMC5665071.
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Oncoimmunology. 2017 Jul 20;6(10):e1353857. doi: 10.1080/2162402X.2017.1353857. eCollection 2017.

PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody.

Oncoimmunology

Laetitia They, Henri-Alexandre Michaud, Ondine Becquart, Virginie Lafont, Bernard Guillot, Florence Boissière-Michot, Marta Jarlier, Caroline Mollevi, Jean-François Eliaou, Nathalie Bonnefoy, Laurent Gros

Affiliations

  1. IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U1194; Université Montpellier; Institut Régional du Cancer de Montpellier, Montpellier, France.
  2. Département de Dermatologie, Centre Hospitalier Universitaire de Montpellier et Faculté de Médecine, Université de Montpellier, Hôpital Saint-Eloi, Montpellier cedex 5, France.
  3. Translational Research Department, Institut Régional du Cancer Montpellier, Montpellier, France.
  4. Biometrics Unit, Institut Régional du Cancer Montpellier, Montpellier, France.
  5. Département d'Immunologie, Centre Hospitalier Universitaire de Montpellier et Faculté de Médecine, Université de Montpellier, Hôpital Saint-Eloi, Montpellier cedex 5, France.

PMID: 29123966 PMCID: PMC5665071 DOI: 10.1080/2162402X.2017.1353857

Abstract

Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy. In immunocompetent mice TA99 treatment strongly increased the fraction of CD8 and CD4 effector T cells in the tumor compared with isotype control, highlighting the specific immune modulation of the tumor microenvironment by TA99. However, in most mice, TA99 immunotherapy could not prevent immune effector exhaustion and the recruitment of regulatory CD4 T cells and consequently tumor escape from immune surveillance. Remarkably, anti-PD-1 treatment at the time of tumor emergence restored the Th1 effector functions of CD4 and CD8 T cells as well as of natural killer and γδT cells, which translated into a significant slow-down of tumor progression and extended survival. Our findings provide the first evidence that PD-1 blockade at the time of tumor emergence can efficiently boost the host anti-tumor immune response initiated several weeks before by the TA-targeting mAb. These results are promising for the design of combined therapies to sensitize non-responder or resistant patients.

Keywords: anti-tumor immunity; combined therapies; immunomodulation; long-lasting effects; tumor escape; tumor immune microenvironment; tumor-targeting monoclonal antibodies

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