Bevacizumab improves the antitumor efficacy of adoptive cytokine-induced killer cells therapy in non-small cell lung cancer models

Cytokine-induced killer cells (CIK cells) are a heterogeneous population of cells generated from peripheral blood mononuclear cells, which share phenotypic and functional properties with both natural killer and T cells. CIK cells therapy, as an adoptive immunotherapy with strong antitumor activity in vitro, represents a promising approach for the treatment of a broad array of malignant tumors. However, clinical trials in CIK cells therapy did not show more noticeable improvement as anticipated in cure rates or long-term survival. Possible explanations are that abnormal tumor vasculature and hypoxic microenvironment may highly limit the therapeutic benefits of CIK cells therapy. We hypothesized that antiangiogenesis therapy could enhance the antitumor efficacy of CIK cells by normalizing tumor vasculature and modulating tumor hypoxic microenvironment. In this study, we combined bevacizumab and adoptive CIK cells therapy in the treatment of lung adenocarcinoma bearing murine models. Flow cytometry, intravital microscopy and immunohistochemistry were applied to detect tumor vasculature and hypoxic microenvironment as well as the infiltration of CIK cells. The results indicated that bevacizumab-combined adoptive CIK cells had synergistic inhibition effects on the growth of lung adenocarcinoma. Hypoxia significantly inhibited the infiltration of CIK cells into tumor tissue. Bevacizumab could normalize tumor vasculature and decrease tumor hypoxic area. Furthermore, combination therapy enhanced more CIK cells infiltrated into tumor compared with other treatment. Bevacizumab improves antitumor efficacy of CIK cells transfer therapy in non-small cell lung cancer (NSCLC). The study provides a reasonable and beneficial strategy that combined antiangiogenesis therapy with CIK cells therapy for patients of advanced stage non-small cell lung cancer.