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Our laboratory has previously demonstrated that adoptive cell transfer (ACT) of melanoma-specific memory T cells (TM) results in a more potent local and systemic T cell response than ACT with melanoma-specific effector T cells (TE). However, we have also seen that TM are not more cytotoxic than TEin vitro. We hypothesized that a combination of TE+M ACT would have an additive effect compared to TE and TM ACT alone.
C57BL/6 mice were inoculated with subcutaneous injections of B16F10 melanoma cells transfected to express low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33). GP33-specific TE, TM, or TE+M ACT was administered seven days after tumor inoculation. Cultured GP33-specific TE, TM, or TE+M were stimulated with GP33 or co-cultured with B16GP33 cells.
Combinatorial TE+M ACT resulted in more potent suppression of in vivo B16GP33 melanoma growth compared to TM or TE ACT alone. TE+M ACT resulted in slightly higher populations of total CD8+ TILs compared with TM ACT. TE+M ACT did not result in higher numbers of exogenously-derived transferred T cells; rather, combination ACT resulted in a profound induction of endogenous TILs. In addition, combination ACT induced the most potent systemic T cell response to tumor antigen. In vitro, TE and TM were comparable in their ability to inhibit of melanoma growth, but TE+M was synergistic. This synergy was reproduced by applying conditioned media derived from activated TM to co-culture wells containing TE. The addition of neutralizing IL-2 antibody negated this effect. TE were more effective at inhibiting melanoma cell growth at early time points, but the strength of this inhibition diminished over time. In contrast, TM became more effective at inhibiting melanoma growth over time.
Overall, these data suggest that a synergistic interaction between TE and TM may promote combinatorial ACT's superior anti-tumor efficacy. Combinatorial ACT's strong endogenous T cell infiltration and systemic response indicates that the combination's synergistic effect is enhancing the host's immune system. Our in vitro results suggest that cytokines released by stimulated TM may augment the local cytotoxicity of TE and that the temporal differences in killing may enhance the combination's ability to inhibit tumor growth. Further investigations will be performed to understand the cellular and molecular mechanisms responsible for this clinically promising observation.