Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model

Abstract

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.

CK1α overexpression correlates with poor survival in colorectal cancer

“…Recently, D4476 has been described as a potent inhibitor of CK1α [ 24 – 26 ] , although previously having been described as CK1δ/ε specific inhibitor [ 27 , 28 ]. Furthermore, the effects of the anticancer drug lenalidomide are partially due to the initiation of proteasomal degradation of CK1α [ 29 , 30 ]. Nevertheless, additional pre-clinical and clinical testing of CK1α inhibitors or agents inducing CK1α degradation or inhibiting the interaction of CK1α with cellular proteins [ 31 ] are urgently needed to further investigate their therapeutic potential.…”

Pomalidomide Inhibits PD-L1 Induction to Promote Antitumor Immunity

“…However, there is substantial evidence suggesting IMiDs exert CRBNindependent functions. IMiDs do not interact with mouse CRBN, but there are many reports showing that IMiDs exert antitumor response in several mouse models (22,23). In our experiments, the expression of PD-L1 was significantly inhibited by pomalidomide in cancer cells from both humans and mice.…”

“…Many of these immunomodulatory functions are presumably mediated through the protease cereblon (CRBN) for the degradation of its downstream targets (21). The in vivo immunomodulatory effects of IMiDs have also been reported in several mouse solid cancer models (22,23), although mouse CRBN is known to not interact with thalidomide-like agents, suggesting a CRBN-independent immunomodulatory effect (24,25). Thus, the exact molecular mechanism, as well as the relative importance of the immunomodulatory effects of thalidomide-like drugs in cancer therapy, is yet to be dissected.…”

Apigenin induces apoptosis by suppressing Bcl-xl and Mcl-1 simultaneously via signal transducer and activator of transcription 3 signaling in colon cancer

“…The current standard treatment for patients with colon cancer is surgical resection followed by chemotherapy (2). However, patients that experience recurrence following surgery or are diagnosed when they are at an advanced stage colon cancer are difficult to treat, despite the development of novel chemotherapeutic regimens and molecular targeted therapy (3). In addition, continuous chemotherapy and molecular targeted therapy induce toxicity in normal tissues.…”