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 ex vivoactivation of bulk T cells typically done with aCD28/aCD3 coated beads.In vitrostudies indicate this method of activation favours the expansion of CD4+T cells, leaving the CD8+T cell component small and displaying an exhaustive phenotype [1]. As a high number of both CD4+and CD8+tumour infiltrating lymphocytes is associated with enhanced tumour regression [2], we investigated alternative methods for in vitroT 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 co-stimulation led to a superior proliferation of the CD8+T cell population. Furthermore, a4-1BB activation of CD8 T cells resulted in significantly higher cytokine and chemokine secretion. The cytotoxic function of CD8+T cells was not altered by the mode of co-stimulation, however, stimulation with both aCD28 and a4-1BB synergised to enhance potency.
In vitro activation with aCD3 and either aCD28 or a4-1BB led to qualitative and quantitative differences in the persistence and expansion of adoptively transferred CD8+T cells.
These results demonstrate that 4-1BB co-stimulation could be preferential to CD28 to direct a robust CD8+T cell response in ACT. These tools interrogating 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 protocols.