Pre-immunization of donor lymphocytes with GITR agonistic antibody enhances antitumor immunity in autologous hematopoietic stem cell transplantation

Abstract The lymphopenic condition following autologous hematopoietic stem cell transplantation (HSCT) enhances the proliferation of T cells by engaging tumor-associated antigens, leading to the alteration of the T-cell repertoire towards antitumor immunity. However, cure by autologous HSCT alone have rarely occurred in the clinical setting. Since tumor- reactive lymphocytespreferentially proliferate during reconstitution of the immune system, we examined whether the priming of donor lymphocytescan strengthen the antitumor effect by HSCT in a CT26 murine colon cancer model. The systemic administration of an anti-glucocorticoid-induced TNF receptor (GITR) agonistic antibody (Ab) significantly increased the number of CT26-responsive T cells but not that of auto- reactive lymphocytesin donor mice. The infusion of non-primed and GITR Ab-primed donor lymphocytessuppressed the CT26 tumor growth, and only the primed lymphocyteseliminated tumors in all the treated mice. The frequency of CT26-responsive T cells was elevated in recipient mice infused with both primed and non-primed lymphocytesuntil 4 weeks after transplantation, while the frequency in recipients with primed lymphocyteswas markedly elevated compared with that in mice harboring non-primed lymphocytesat 2 weeks. The frequencies of regulatory T cells and myeloid-derived suppressor cellswere elevated in recipient mice infused with primed and non-primed lymphocytes2 weeks after transplantation, and returned to normal levels by week 4. The combination of autologous HSCT with pre-immunization of donor lymphocytesis a promising strategy to induce strong antitumor immunity.