Co-transfer of tumor-specific CD8+ Teff and Tmem cells by Contreras et al. led to the strongest control of tumor growth in a B16F10 murine model in comparison to transfer of either alone. Co-transfer produced the strongest intratumoral infiltration by endogenous CD8+ T cells and the greatest antigen-specific expression of IFNγ in splenocytes. Paracrine release of IL-2 from Tmem also appeared to increase Teff inhibition of melanoma cell proliferation, and temporal differences in ability of Tmem and Teff to inhibit proliferation may have contributed to the success of the combination.

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.

Author Info: (1) Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, 2015 Linden Drive, Madison, WI, 53706, USA. (2) Department of Surgery, University of

Author Info: (1) Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, 2015 Linden Drive, Madison, WI, 53706, USA. (2) Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI, 53792, USA. (3) Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI, 53792, USA. (4) Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI, 53792, USA. (5) Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI, 53792, USA. (6) Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, 2015 Linden Drive, Madison, WI, 53706, USA. (7) VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI, 48105, USA. Department of Surgery, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA. (8) VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI, 48105, USA. cliffcho@med.umich.edu. Department of Surgery, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA. cliffcho@med.umich.edu.

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