Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer

C Dai, F Lin, R Geng, X Ge, W Tang, J Chang, Z Wu, X Liu, Y Lin, Z Zhang, J Li

Research output: Contribution to journalArticle

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Abstract

Cytokine-induced killer (CIK) cells represent a realistic approach in cancer immunotherapy with confi rmed survival benefi ts in the context of metastatic solid tumors. However, therapeutic effects are limited to a fraction of patients. In this study, immune-resistance elements and ideal combination therapies were explored. Initially, phenotypic analysis was performed to document CD3, CD56, NKG2D, DNAM- 1, PD-L1, PD-1, CTLA-4, TIM-3, 2B4, and LAG-3 on CIK cells. Upon engagement of CIK cells with the tumor cells, expression of PD-1 on CIK cells and PD-L1 on both cells were up-regulated. Over-expression of PD-L1 levels on tumor cells via lentiviral transduction inhibited tumoricidal activity of CIK cells, and neutralizing of PD-L1/ PD-1 signaling axis could enhance their tumor-killing effect. Conversely, blockade of NKG2D, a major activating receptor of CIK cells, largely caused dysfunction of CIK cells. Functional study showed an increase of NKG2D levels along with PD-L1/PD-1 blockade in the presence of other immune effector molecule secretion. Additionally, combined therapy of CIK infusion and PD-L1/PD-1 blockade caused a delay of in vivo tumor growth and exhibited a survival advantage over untreated mice. These results provide a preclinical proof-of-concept for simultaneous PD-L1/PD-1 pathways blockade along with CIK infusion as a novel immunotherapy for unresectable cancers.
Original languageEnglish
Pages (from-to)10332-10344
Number of pages13
JournalOncotarget
Volume7
Issue number9
DOIs
Publication statusPublished - 2016

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Cytokine-Induced Killer Cells
Gastrointestinal Neoplasms
Immunotherapy
Neoplasms
Cytokines
Survival
Therapeutic Uses

Cite this

Dai, C ; Lin, F ; Geng, R ; Ge, X ; Tang, W ; Chang, J ; Wu, Z ; Liu, X ; Lin, Y ; Zhang, Z ; Li, J. / Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer. In: Oncotarget. 2016 ; Vol. 7, No. 9. pp. 10332-10344.
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abstract = "Cytokine-induced killer (CIK) cells represent a realistic approach in cancer immunotherapy with confi rmed survival benefi ts in the context of metastatic solid tumors. However, therapeutic effects are limited to a fraction of patients. In this study, immune-resistance elements and ideal combination therapies were explored. Initially, phenotypic analysis was performed to document CD3, CD56, NKG2D, DNAM- 1, PD-L1, PD-1, CTLA-4, TIM-3, 2B4, and LAG-3 on CIK cells. Upon engagement of CIK cells with the tumor cells, expression of PD-1 on CIK cells and PD-L1 on both cells were up-regulated. Over-expression of PD-L1 levels on tumor cells via lentiviral transduction inhibited tumoricidal activity of CIK cells, and neutralizing of PD-L1/ PD-1 signaling axis could enhance their tumor-killing effect. Conversely, blockade of NKG2D, a major activating receptor of CIK cells, largely caused dysfunction of CIK cells. Functional study showed an increase of NKG2D levels along with PD-L1/PD-1 blockade in the presence of other immune effector molecule secretion. Additionally, combined therapy of CIK infusion and PD-L1/PD-1 blockade caused a delay of in vivo tumor growth and exhibited a survival advantage over untreated mice. These results provide a preclinical proof-of-concept for simultaneous PD-L1/PD-1 pathways blockade along with CIK infusion as a novel immunotherapy for unresectable cancers.",
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Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer. / Dai, C; Lin, F; Geng, R; Ge, X; Tang, W; Chang, J; Wu, Z; Liu, X; Lin, Y; Zhang, Z; Li, J.

In: Oncotarget, Vol. 7, No. 9, 2016, p. 10332-10344.

Research output: Contribution to journalArticle

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