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Isolation and Expansion of Cytotoxic Cytokine-induced Killer T Cells for Cancer Treatment
Published on: January 24, 2020
Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target
Giulia Mesiano1, Giovanni Grignani1, Erika Fiorino2
1Medical Oncology Division, Candiolo Cancer Institute, FPO-IRCCS. Str. Prov. 142, km 3.95, I-10060, Candiolo (To), Italy.
Abstract:
Metastatic bone and soft tissue sarcomas often relapse after chemotherapy (CHT) and molecular targeted therapy (mTT), maintaining a severe prognosis. A subset of sarcoma cancer stem cells (sCSC) is hypothesized to resist conventional drugs and sustain disease relapses. We investigated the immunotherapy activity of cytokine induced killer cells (CIK) against autologous sCSC that survived CHT and mTT. The experimental platform included two aggressive bone and soft tissue sarcoma models: osteosarcoma (OS) and undifferentiated-pleomorphic sarcoma (UPS). To visualize putative sCSC we engineered patient-derived sarcoma cultures (2 OS and 3 UPS) with a lentiviral sCSC-detector wherein the promoter of stem-gene Oct4 controls the expression of eGFP. We visualized a fraction of sCSC (mean 24.2 ± 5.2%) and confirmed their tumorigenicity in vivo. sCSC resulted relatively resistant to both CHT and mTT in vitro. Therapeutic doses of doxorubicin significantly enriched viable eGFP+sCSC in both OS (2.6 fold, n = 16) and UPS (2.3 fold, n = 29) compared to untreated controls. Treatment with sorafenib (for OS) and pazopanib (for UPS) also determined enrichment (1.3 fold) of viable eGFP+sCSC, even if less intense than what observed after CHT. Sarcoma cells surviving CHT and mTT were efficiently killed in vitro by autologous CIK even at minimal effector/target ratios (40:1 = 82%, 1:4 = 29%, n = 13). CIK immunotherapy did not spare sCSC that were killed as efficiently as whole sarcoma cell population. The relative chemo-resistance of sCSC and sensitivity to CIK immunotherapy was confirmed in vivo. Our findings support CIK as an innovative, clinically explorable, approach to eradicate chemo-resistant sCSC implicated in tumor relapse.
Insights
Cytokine-induced killer (CIK) cells show promise in eradicating chemo-resistant sarcoma stem cells (sCSC) that often cause relapse after chemotherapy and targeted therapy. This immunotherapy offers a potential new approach for treating aggressive bone and soft tissue sarcomas.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Stem Cell Biology
Background:
- Metastatic bone and soft tissue sarcomas frequently relapse post-chemotherapy and targeted therapy, leading to poor prognoses.
- Sarcoma cancer stem cells (sCSC) are implicated in treatment resistance and disease recurrence.
- Existing therapies often fail to eliminate these resistant sCSC populations.
Purpose of the Study:
- To investigate the efficacy of cytokine-induced killer (CIK) cells against autologous sarcoma cancer stem cells (sCSC) surviving conventional treatments.
- To evaluate the resistance of sCSC to chemotherapy (CHT) and molecular targeted therapy (mTT) in osteosarcoma (OS) and undifferentiated-pleomorphic sarcoma (UPS) models.
Main Methods:
- Engineered patient-derived sarcoma cultures (OS and UPS) with a lentiviral sCSC-detector (Oct4-eGFP) to visualize and quantify sCSC.
- Assessed sCSC enrichment and viability after in vitro treatment with doxorubicin, sorafenib, and pazopanib.
- Evaluated the in vitro and in vivo killing capacity of autologous CIK cells against sCSC and bulk sarcoma cells.
Main Results:
- Sarcoma cancer stem cells (sCSC) were visualized and confirmed as tumorigenic, exhibiting relative resistance to CHT and mTT.
- Chemotherapy (doxorubicin) and targeted therapies (sorafenib, pazopanib) significantly enriched viable sCSC populations.
- Autologous CIK cells efficiently killed both bulk sarcoma cells and chemo-resistant sCSC in vitro and in vivo, even at low effector/target ratios.
Conclusions:
- Sarcoma cancer stem cells (sCSC) are relatively resistant to conventional chemotherapy and targeted therapy but are susceptible to CIK immunotherapy.
- CIK immunotherapy demonstrates potential as a novel strategy to eradicate chemo-resistant sCSC, addressing a key mechanism of tumor relapse.
- Findings support the clinical exploration of CIK cells for treating metastatic bone and soft tissue sarcomas.
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