Imatinib Mesylate Exerted Antitumor Effect by Promoting Infiltration of Effector T Cells in Tumor.

Imatinib mesylate is a potent tyrosine kinase inhibitor that may induce immunological effects, such as inhibition of immune suppressive cells; but, how it modulates the immune system remains to be completely elucidated. In this study, we showed that cell proliferation of CT26 colon cancer and Lewis lung carcinoma (3LL) lung cancer cells was not inhibited by imatinib in vitro, although its administration significantly suppressed the growth of CT26, but not 3LL, subcutaneous tumors, and prolonged survival in CT26 tumor-bearing mice. Further, we examined the expression of immune cell-related molecules in the tumors to elucidate the differences in imatinib-mediated antitumor effects between CT26 and 3LL tumors. The nCounter assay showed that the expression of CD8 and CD8+ T cell-recruiting chemokine genes was significantly elevated in imatinib-treated CT26 tumors than that in control tumors; however, the gene expression remained unchanged in imatinib-treated or control 3LL tumors. Furthermore, frequency of interferon-γ+ (IFN-γ+) CD8+ T cells was increased in imatinib-treated CT26 tumors than control tumors, indicating induction of antitumor immunity by imatinib. The analysis indicates that imatinib promotes infiltration of effector T cells in tumors by upregulating expression of cytokines that recruit CD8+ T cells in the tumor microenvironment, which may lead to a strong antitumor effect.

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

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 lymphocytes preferentially proliferate during reconstitution of the immune system, we examined whether the priming of donor lymphocytes can 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 lymphocytes in donor mice. The infusion of non-primed and GITR Ab-primed donor lymphocytes suppressed the CT26 tumor growth, and only the primed lymphocytes eliminated 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 lymphocytes until 4 weeks after transplantation, while the frequency in recipients with primed lymphocytes was markedly elevated compared with that in mice harboring non-primed lymphocytes at 2 weeks. The frequencies of regulatory T cells and myeloid-derived suppressor cells were elevated in recipient mice infused with primed and non-primed lymphocytes 2 weeks after transplantation, and returned to normal levels by week 4. The combination of autologous HSCT with pre-immunization of donor lymphocytes is a promising strategy to induce strong antitumor immunity.