RESUMO
In this study, we investigated efficacy of lenalidomide in combination with tumor antigen-loaded dendritic cells (DCs) in murine colon cancer model. MC-38 cell lines were injected subcutaneously to establish colon cancer-bearing mice. After tumor growth, lenalidomide (50 mg/kg/day) was injected intraperitoneally on 3 consecutive days in combination with tumor antigen-loaded DC vaccination on days 8, 12, 16, and 20. The tumor antigen-loaded DCs plus lenalidomide combination treatment exhibited a significant inhibition of tumor growth compared with the other groups. These effects were associated with a reduction in immune suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, with the induction of immune effector cells, such as natural killer cells, CD4+ T cells and CD8+ T cells in spleen, and with the activation of cytotoxic T lymphocytes and NK cells. This study suggests that a combination of tumor antigen-loaded DC vaccination and lenalidomide synergistically enhanced antitumor immune response in the murine colon cancer model, by inhibiting the generation of immune suppressive cells and recovery of effector cells, and demonstrated superior polarization of Th1/Th2 balance in favor of Th1 immune response. This combination approach with DCs and lenalidomide may provide a new therapeutic option to improve the treatment of colon cancer.
Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Células Dendríticas/imunologia , Imunidade , Talidomida/análogos & derivados , Animais , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Terapia Combinada , Citocinas/biossíntese , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Imunidade/efeitos dos fármacos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Lenalidomida , Camundongos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Talidomida/farmacologia , VacinaçãoRESUMO
Lenalidomide (LEN) has been used as an immunomodulatory drug with direct and indirect anti-tumor effects. In this study, we evaluated the effect of LEN on the differentiation, maturation, and function of dendritic cells (DCs) in patients with multiple myeloma in vitro. Various doses of LEN were added after the monocytes had differentiated into immature DCs and were activated into mature DCs. LEN (5 µg/mL) was the optimal concentration to promote differentiation and maturation of DCs. Immature DCs treated with LEN exhibited enhanced endocytic capacity. Mature DCs treated with LEN produced higher levels of interleukin-12p70, possessed stronger allogeneic T-cell stimulation capacity, reduced the number of suppressor cells, and generated antigen-specific cytotoxic T lymphocytes more potently compared with control DCs. These results suggest that LEN enhanced the function of DCs generated from patients with multiple myeloma by stimulating the capacity of allogeneic T cells, inhibiting the generation of immunosuppressive cells, inducing naïve T cells toward Th1 polarization, and generating potent myeloma-specific cytotoxic T lymphocytes.
