Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model

Amanda Contreras, Megan V. Beems, Andrew J. Tatar, Siddhartha Sen, Prakrithi Srinand, M. Suresh, Tahra K. Luther, Clifford S. Cho

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Adoptive cell transfer (ACT) is a promising cancer immunotherapeutic strategy that remains ineffective for a large subset of patients. ACT with memory CD8+ T cells (Tmem) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (Teff). Teff and Tmem have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of Teff and Tmem. Methods: Splenocytes harvested from Ly5.1+/C57BL/6 mice during and after infection with lymphocytic choriomeningitis virus (LCMV) were used to generate bona fide effector and memory CD8+ T cells specific for the LCMV epitope peptide GP33. Congenic Ly5.2+/C57BL/6 mice were inoculated with B16F10 melanoma cells transfected to express very low levels of GP33, then treated with ACT 7 days later with GP33-specific Teff, Tmem, or a combination of Teff+Tmem. Results: Inhibition of melanoma growth was strongest in mice receiving combinatorial ACT. Although combinatorial ACT and memory ACT resulted in maximal intratumoral infiltration of CD8+ T cells, combinatorial ACT induced stronger infiltration of endogenous CD8+ T cells than Tmem ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with Teff and gradual but prolonged melanoma inhibition with Tmem; the addition of Tmem enhanced the ability of Teff to inhibit melanoma in a manner that could be reproduced using conditioned media from activated Tmem and blocked by the addition of anti-IL-2 blocking antibody. Conclusions: These findings suggest that a novel combinatorial approach that takes advantage of the unique and complementary strengths of tumor-specific Teff and Tmem may be a way to optimize the efficacy of adoptive immunotherapy.

Original languageEnglish (US)
Article number41
JournalJournal for ImmunoTherapy of Cancer
Volume6
Issue number1
DOIs
StatePublished - May 29 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grant support from the Department of Veterans Affairs CDA-2 and Merit Review Award (1I01BX001619-01A1) to CSC, National Institutes of Health T32 (CA090217) to MVB, National Institutes of Health T32 (GM081061 and AI55397) to AC, and National Institutes of Health AI48785 to MS. 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

Funding Information:
This work was supported by grant support from the Department of Veterans Affairs CDA-2 and Merit Review Award (1I01BX001619-01A1) to CSC, National Institutes of Health T32 (CA090217) to MVB, National Institutes of Health T32 (GM081061 and AI55397) to AC, and National Institutes of Health AI48785 to MS. 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.

Publisher Copyright:
© 2018 The Author(s).

Keywords

  • Adoptive transfer
  • Cancer
  • Effector
  • Immunotherapy
  • Melanoma
  • Memory
  • T cell

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