Low-dose controlled release of mTOR inhibitors maintains T cell plasticity and promotes central memory T cells

Abstract

An important goal for improving vaccine and immunotherapy technologies is the ability to provide further control over the specific phenotypes of T cells arising from these agents. Along these lines, frequent administration of rapamycin (Rapa), a small molecule inhibitor of the mammalian target of rapamycin (mTOR), exhibits a striking ability to polarize T cells toward central memory phenotypes (TCM), or to suppress immune function, depending on the concentrations and other signals present during administration. TCM exhibit greater plasticity and proliferative capacity than effector memory T cells (TEFF) and, therefore, polarizing vaccine-induced T cells toward TCM is an intriguing strategy to enhance T cell expansion and function against pathogens or tumors. Here we combined biodegradable microparticles encapsulating Rapa (Rapa MPs) with vaccines composed of soluble peptide antigens and molecular adjuvants to test if this approach allows polarization of differentiating T cells toward TCM. We show Rapa MPs modulate DC function, enhancing secretion of inflammatory cytokines at very low doses, and suppressing function at high doses. While Rapa MP treatment reduced – but did not stop – T cell proliferation in both CD4+ and CD8+ transgenic T cell co-cultures, the expanding CD8+ T cells differentiated to higher frequencies of TCM at low doses of MP Rapa MPs. Lastly, we show in mice that local delivery of Rapa MPs to lymph nodes during vaccination either suppresses or enhances T cell function in response to melanoma antigens, depending on the dose of drug in the depots. In particular, at low Rapa MP doses, vaccines increased antigen-specific TCM, resulting in enhanced T cell expansion measured during subsequent booster injections over at least 100days.