Progression of Large Lymphoma Is Significantly Impeded with a Combination of Gemcitabine Chemotherapy and Dendritic Cells Intra-Tumor Vaccination.

Abstract

Relapsed, refractory lymphoma remains to be a challenge and lacks efficient treatment. Some tumor cells escape from treatment, become resistant to chemotherapeutic agents, and rapidly regenerate into large tumors. Lymphoma cells induce accumulation of Gr-1(+-)CD11b(+) myeloid derived suppressor cells (MDSCs) in lymphatic organs and their vicinity. MDSCs enable tumor cells to escape from immune cells mediated surveillance and attack. Gemcitabine is a chemotherapeutic agent that eliminates both tumor cells and MDSCs, improving the immune environment favorable for subsequent treatment. We evaluated the effects of low dose gemcitabine combined with intra-tumorally delivered dendritic cells (DCs) for the treatment of A20 large-size lymphoma. We showed that MDSCs increased markedly in lymphoma-bearing mice, and that gemcitabine significantly increased the apoptosis of MDSCs. Treatment of lymphoma with either gemcitabine or intra-tumoral DCs alone could not inhibit tumor growth or rescue lymphoma-bearing mice. Treatment of lymphoma with small dose gemcitabine followed by intra-tumorally injected DCs significantly improved the efficacy of either individual treatment by reducing MDSCs, inducing onsite DCs maturation, eliminating tumor cells, inhibiting tumor growth and relapse, and extending the survival of the lymphoma-bearing mice, partly through the induction of the IFNγ secreting cells and the activation of cytotoxic lymphocytes. We showed that NK cells and CD8(+ )T cells were the major effectors to mediate the inhibition of tumor growth. Thus, the observation that gemcitabine synergizes DCs mediated immunotherapy to improve the efficacy of large size lymphoma treatment provides an experimental basis for the combination of chemotherapy and immunotherapy for the efficient treatment of relapsed or refractory lymphoma.