Synergistic antitumor effect of combining metronomic chemotherapy with adoptive cell immunotherapy in nude mice

Abstract

Adoptive cell immunotherapy with cytokine-induced killer cell (CIK cell) represents a promising non-toxic anticancer therapy. However, the clinical efficacy of CIK cells is limited because of abnormal tumor vasculature. Metronomic chemotherapy shows promising anticancer activity by its potential antiangiogenic effect and reduced toxicity. We hypothesized that metronomic chemotherapy with paclitaxel could improve the antitumor effect of adoptive CIK cell immunotherapy. Mice health status was analyzed by measuring mice weight and observing mice behavior. Immunohistochemistry was used to investigate the recruitment of CIK cells, the expression of endothelial cell molecules, as well as the hypoxic tumor area. Metronomic paclitaxel synergized with adoptive CIK cell immunotherapy to inhibit the growth of non-small cell lung cancer (NSCLC). Metronomic paclitaxel reduced hypoxic tumor area and increased CIK cell infiltration. Hypoxia impeded the adhesion of CIK cells and reduced the expression of endothelial cell adhesion molecules. In vivo studies demonstrated that more CIK cells were found in endothelial cell adhesion molecules high expressed area. Our study provides a new rationale for combining metronomic chemotherapy with adoptive cell immunotherapy in the treatment of xenograft NSCLC tumors in immunodeficient mice. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach.

Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15

“…2). Though moderate, the reduction in tumor growth, given similar cellular doses, was consistent with that observed in pre-clinical models of CIK for NSCLC in the absence of additional interventions [24–26], but differ from the ability of CAR-T cells to reduce established tumor growth [12, 27].…”

Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells

“…Recently, some studies have proven that combination of antiangiogenesis therapy with immunotherapy could have better antitumor effects in lung adenocarcinoma, indicating tumor immunosuppression and angiogenesis might be tightly connected31323334. In conclusion, hypoxia of lung adenocarcinoma cells could induce both tumor immunosuppression and angiogenesis through the up-regulation of CCL28.…”

“…Taken together, at least two major roles are played by CCL28 in lung adenocarcinoma, including immunosuppression and pro-angiogenesis (directly and indirectly), both of which are important targets for cancer therapy. Recently, some studies have proven that combination of antiangiogenesis therapy with immunotherapy could have better antitumor effects in lung adenocarcinoma, indicating tumor immunosuppression and angiogenesis might be tightly connected 31 32 33 34 . In conclusion, hypoxia of lung adenocarcinoma cells could induce both tumor immunosuppression and angiogenesis through the up-regulation of CCL28.…”

Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer?

“…In murine models of ovarian cancer under gemcitabine or paclitaxel, it was shown that gemcitabine decreased the number of MDSCs, while paclitaxel did not. 28 …”

“…In murine models of ovarian cancer under gemcitabine or paclitaxel, it was shown that gemcitabine decreased the number of MDSCs, while paclitaxel did not. 28 Based on these findings, different clinical trials evaluating the safety and efficacy of platinumbased chemotherapy with immune checkpoint inhibitors have been designed.…”