Adoptive cell therapy (ACT) is a type of immunotherapy used to successfully treat a wide range of cancers by direct targeting or enhancing of the immune response. ACT requires clinical activation of T cells by co-culture with aCD28/aCD3 coated beads. In vitro studies indicate this method of activation favours the expansion of CD4 T cells with an exhaustive phenotype [1]. We investigated alternative methods for in vitro T cell activation, to determine if diverse T cell fates could be achieved through varying signals received by T cells upon activation.
Using quantitative assays for T cell proliferation, we found that 4-1BB as opposed to CD28 led to a superior proliferation of the CD8 T cell population. Furthermore, 4-1BB co-stimulation of CD8 T cells resulted in significantly higher cytokine and chemokine secretion. The functional cytotoxicity of CD8 T cells was not influenced by the mode of co-stimulation, however, aCD28 and a4-1BB synergized to enhance potency.
To study functional differences in vivo, we measured persistence of in vitro activated and then adoptively transferred CD8 T cells in C57BL/6 mice. We found that compared to aCD28, 4-1BB co-stimulation led to enhanced persistence and a greater central memory phenotype of the circulating T cell pool. Additionally, when tumour specific T cells were activated with a4-1BB there was a greater accumulation of transferred T cells at tumour sites than aCD28 activated T cells in mouse tumour models.
These results demonstrate that 4-1BB co-stimulation would be preferential to CD28 to direct a robust CD8 T cell response in ACT. These tools we have developed to interrogate T cell activation, will allow for a better understanding of the biology underpinning how a T cell integrates co-stimulatory signals during priming. This unlocks the potential to ‘tailor’ design current clinical practice and informatively predict the T cell response for ACT.