Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells

Abstract

This work reports the effective antitumor activity of patient-derived cytokine-induced killer (CIK) cells against autologous chemo-resistant melanoma Cancer Stem Cells (CSCs).CSCs are clinical relevant targets, associated with disease relapse. We demonstrate that chemotherapy kills indeed proliferating melanoma cells but spares tumorigenic CSCs, in vitro and in vivo. The MHCindependent immunotherapy with CIK cells was proved successful in this challenging framework.Consistent findings were obtained in selected cases of BRAF mutated melanoma treated with small molecule BRAFi. Our data, generated within an autologous system, support the exploration of CIK cells in clinical trials. Cost effectiveness, safety profile and ability to overcome tumor MHC-downregulation are favorable issues to be considered in clinical perspective. CIK cells may be integrated at different levels in the composite therapeutic scenario of metastatic melanoma, offering an additional weapon to control tumor spread and promote its eradication. ABSTRACT PurposeThe MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSCs) was explored, as CSCs are considered responsible for chemo-resistance and relapses. Experimental designPutative mCSCs were visualized by engineering patient-derived melanoma cells (MCs) with a lentiviralvector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays.We explored the sensitivity of eGFP CIK cell activity against chemoresistant mCSCs was confirmed vivo in two distinct immunodeficient murine models. ResultsWe visualized eGFP + mCSCs (14±2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP-positive MCs (1/42) compared with the eGFP-negative counterpart (1/4870).In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells ( ConclusionsThese findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving chemotherapy or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided.

Efficacy of adjuvant cytokine-induced killer cell immunotherapy in patients with colorectal cancer after radical resection

“…Besides, CIK cells can enhance the efficacy of chemotherapy in patients by eliminating potential or residual tumor cells including even drug-resistant tumor cells and putative cancer stem cells. 31,32 Furthermore, CIK cell treatment can improve the immunological status of patients with CRC. 33 Our results also suggested that the percentages of CD3 + CD56 + subsets, representing the main anti-tumor immuno-effector cells, 34,35 significantly increased after the fourth treatment cycle in patients with CRC.…”

Retrospective analysis of the efficacy of cytokine‐induced killer cell immunotherapy combined with first‐line chemotherapy in patients with metastatic colorectal cancer

“…In turn, the activation of infused CIK cells will also be affected by the immune microenvironment in vivo. CIK cells are a heterogeneous cell population, containing CD3 + CD4 + , CD3 + CD8 + , CD3 + CD56 + and CD3 − CD56 + cell subsets; therefore, we explored whether the CIK cell phenotype could serve as a predictor of the efficacy of the combination of CIK cell immunotherapy and first‐line chemotherapy among patients with mCRC. Our previous study found that none of these four cell subsets were associated with survival benefit in patients with colorectal cancer who received adjuvant CIK cell treatment .…”

Retrospective analysis of the efficacy of adjuvant CIK cell therapy in epithelial ovarian cancer patients who received postoperative chemotherapy

“…Residual post-surgery cancer cells have been considered a main origin of cancer recurrence, and some may even develop resistance to chemotherapy. [37][38][39] Recent studies have shown that chemo-resistant cancer cells are sensitive to the cytotoxic effect of CIK cells, 40,41 and thus, theoretically, CIK cells may be potent in eradicating residual tumor cells following surgery and chemotherapy. In this study, we showed that patients with residual tumor ≥ 1 cm yielded more favorable PFS rates from CIT.…”