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Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice

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Abstract

Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy.

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Abbreviations

ACT:

Adoptive cell transfer

LCMV:

Lymphocytic choriomeningitis virus

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Acknowledgments

This work was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Science Research and Development Service, CDA-2 and Merit Review Award (1I01BX001619-01A1) (Cho), by the generous support of Ronald and Patricia A Kissinger (Cho), University of Wisconsin Cellular and Molecular Pathology Training Program and National Institutes of Health (NIH) Grant T32 GM081061 (Contreras), and NIH Grant AI48785 (Suresh). The content is solely the responsibility of the authors and does not represent the views of the Department of Veterans Affairs or the United States Government or the National Institutes of Health.

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Authors and Affiliations

  1. Section of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, J4/703 Clinical Sciences Center, 600 Highland Avenue, Madison, WI, 53792-7375, USA

    Amanda Contreras, Siddhartha Sen, Andrew J. Tatar, David A. Mahvi, Justin V. Meyers, Prakrithi Srinand & Clifford S. Cho

  2. Surgical Service, William S. Middleton Memorial VA Hospital, Madison, WI, USA

    Siddhartha Sen, Andrew J. Tatar & Clifford S. Cho

  3. Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, Madison, WI, USA

    Marulasiddappa Suresh

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  1. Amanda Contreras
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Correspondence to Clifford S. Cho.

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Contreras, A., Sen, S., Tatar, A.J. et al. Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice. Cancer Immunol Immunother 65, 601–611 (2016). https://doi.org/10.1007/s00262-016-1823-8

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