Influence of PD-1 monoclonal antibody on anti-lung cancer effect of cytokine-induced killer cells (CIK) induced and expanded <i>in vitro</i>_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LIU Tong ^1,2 , WANG Heshuang ³ ,  XU Ning ²

1. Graduate School of Dalian Medical University, Dalian, 116044, Liaoning, P.R.China;
2. Department of Thoracic Surgery, Dalian Municipal Central Hospital Affiliated to Dalian Medical University, Dalian, 116044, Liaoning, P.R.China;
3. Department of Central Laboratory, Dalian Municipal Central Hospital Affiliated to Dalian Medical University, Dalian, 116044, Liaoning, P.R.China;

Corresponding author：

XU Ning, Email: Pierrexu@163.com

Keywords：

PD-1 monoclonal antibody; cytokine-induced killer cells (CIK); lung cancer; immunotherapy

DOI：

10.7507/1007-4848.202006043

Video：

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Objective To investigate the influence of programmed cell death protein-1 (PD-1) monoclonal antibody on the anti-lung cancer effect of cytokine-induced killer cells (CIK) which were programmed in vitro. Methods Peripheral blood mononuclear cells from 20 patients (8 males and 12 females with an average age of 56.45±5.89 years ranging from 42 to 65 years) diagnosed with advanced lung cancer from January to May 2019 at the Department of Oncology of Dalian Central Hospital were collected and induced to amplify into CIK cells in vitro. PD-1 monoclonal antibody combined with CIK cell culture group, individual cell culture group and PD-1 monoclonal antibody group were set up to detect the cell killing activity of CIK cells against lung cancer under different effective target ratio conditions, and the ratio of perforin and granzyme positive expression in PD-1 monoclonal antibody combined CIK cell culture group and individual CIK cell culture group was detected by flow cytometry. ELISA method was used to detect the interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) cytokine secretion levels in the two groups.Results The killing effect of CIK cells on A549 lung cancer cells increased with the increase of effective target ratio by CCK8, and PD-1 monoclonal antibody increased the killing effect of CIK cells on A549 lung cancer cells under different effective target ratio, E∶T=5∶1 (28.5%±1.9% vs. 20.3%±1.8%), 10∶1 (40.6%±2.4% vs. 31.7%±2.1%), 20∶1 (57.4%±3.5% vs. 44.7%±3.8%), 40∶1 (74.1%±8.3% vs. 60.8%±5.3%). The killing effect of PD-1 monoclonal antibody combined with CIK cells and CIK cells alone on A549 lung cancer cells was statistically different (P<0.05). The killing effect of cells in both groups on lung cancer A549 cells was stronger than that of the PD-1 monoclonal antibody group (P<0.01). The results of flow cytometry showed that PD-1 monoclonal antibody increased the positive ratio of perforin and granzyme release in CIK cells, and the positive ratios of perforin release (46.7%±3.5%% vs. 35.1%±2.2%) and granzyme release (34.6%±3.8% vs. 25.7%±3.3%) in PD-1 monoclonal antibody combination with CIK cells group and CIK cells group were statistically different (P<0.05). Similarly, the secretion levels of IL-2, TNF-α, and IFN-γ cytokines were also increased in the PD-1 monoclonal antibody combined with CIK cells group compared with the CIK group (5 409.0±168.8 pg/mL vs. 4 300.0±132.3 pg/mL, 252.7±16.7 pg/mL vs. 172.5±8.6 pg/mL, 327.2±23.5 pg/mL vs. 209.7±16.0 pg/mL, P<0.05).Conclusion PD-1 monoclonal antibody can promote the release of tumoricidal substances in CIK cells and improve the killing effect of CIK cells on lung cancer A549 cells. It is speculated that the infusion of PD-1 monoclonal antibody before CIK cell adoption in lung cancer patients may be more beneficial to the treatment of disease. PD-1 monoclonal antibody combined with CIK cell therapy is promising as a new type of lung cancer immunotherapy.

Citation： LIU Tong, WANG Heshuang, XU Ning. Influence of PD-1 monoclonal antibody on anti-lung cancer effect of cytokine-induced killer cells (CIK) induced and expanded in vitro. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(8): 990-997. doi: 10.7507/1007-4848.202006043 Copy

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2.	Testa U, Castelli G, Pelosi E. Lung cancers: Molecular characterization, clonal heterogeneity and evolution, and cancer stem cells. Cancers (Basel), 2018, 10(8): 248.
3.	Byers LA, Rudin CM. Small cell lung cancer: Where do we go from here? Cancer, 2015, 121(5): 664-672.
4.	Sabari JK, Lok BH, Laird JH, et al. Unravelling the biology of SCLC: Implications for therapy. Nat Rev Clin Oncol, 2017, 14(9): 549-561.
5.	Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol, 2019, 12(1): 47.
6.	Shi L, Zhou Q, Wu J, et al. Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother, 2012, 61(12): 2251-2259.
7.	Yu X, Zhao H, Liu L, et al. A randomized phaseⅡstudy of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol, 2014, 34(2): 194-203.
8.	Brand JM, Meller B, Von Hof K, et al. Kinetics and organ distribution of allogeneic natural killer lymphocytes transfused into patients suffering from renal cell carcinoma. Stem Cells Dev, 2004, 13(3): 307-314.
9.	Dai C, Lin F, Geng R, et al. Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer. Oncotarget, 2016, 7(9): 10332-10344.
10.	Poh SL, Linn YC. Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. Cancer Immunol Immunother, 2016, 65(5): 525-536.
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13.	Yang L, Wang L, Zhang Y. Immunotherapy for lung cancer: Advances and prospects. Am J Clin Exp Immunol, 2016, 5(1): 1-20.
14.	Jiang J, Wu C, Lu B. Cytokine-induced killer cells promote antitumor immunity. J Transl Med, 2013, 11(1): 83.
15.	Méndez R, Ruiz-Cabello F, Rodríguez T, et al. Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy. Cancer Immunol Immunother, 2007, 56(1): 88-94.
16.	Wongkajornsilp A, Somchitprasert T, Butraporn R, et al. Human cytokine-induced killer cells specifically infiltrated and retarded the growth of the inoculated human cholangiocarcinoma cells in SCID mice. Cancer Invest, 2009, 27(2): 140-148.
17.	Thanendrarajan S, Nowak M, Abken H, et al. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: More than one plus one? Leuk Res, 2011, 35(9): 1136-1142.
18.	Schmidt-Wolf IG, Negrin RS, Kiem HP, et al. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med, 1991, 174(1): 139-149.
19.	Linn YC, Wang SM, Hui KM. Comparative gene expression profiling of cytokine-induced killer cells in response to acute myloid leukemic and acute lymphoblastic leukemic stimulators using oligonucleotide arrays. Exp Hematol, 2005, 33(6): 671-681.
20.	Remark R, Becker C, Gomez JE, et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med, 2015, 191(4): 377-390.
21.	Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 2016, 375(18): 1767-1778.
22.	Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection J. Nature, 2006, 439(7077): 682-687.
23.	Misra P, Singh S. Role of cytokines in combinatorial immunotherapeutics of non‐small cell lung cancer through systems perspective. Cancer Med-US, 2019, 8(5): 1976-1995.
24.	Yuan M, Huang LL, Chen JH, et al. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther, 2019, 4(1): 1-14.
25.	Ding X, Cao H, Chen X, et al. Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer. J Transl Med, 2015, 13(1): 158.
26.	Ma W, Gilligan BM, Yuan J, et al. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hemato Oncol, 2016, 9(1): 47.
27.	Qin A, Coffey DG, Warren EH, et al. Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer. Cancer Med-US, 2016, 5(9): 2567-2578.
28.	Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol, 2004, 22: 329-360.
29.	Sui X, Ma J, Han W, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget, 2015, 6(23): 19393-19404.
30.	Teng F, Meng X, Kong L, et al. Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. Cancer Lett, 2018, 414: 166-173.

1. 郑荣寿, 孙可欣, 张思维, 等. 2015 年中国恶性肿瘤流行情况分析. 中华肿瘤杂志, 2019, 41(1): 19-28.
2. Testa U, Castelli G, Pelosi E. Lung cancers: Molecular characterization, clonal heterogeneity and evolution, and cancer stem cells. Cancers (Basel), 2018, 10(8): 248.
3. Byers LA, Rudin CM. Small cell lung cancer: Where do we go from here? Cancer, 2015, 121(5): 664-672.
4. Sabari JK, Lok BH, Laird JH, et al. Unravelling the biology of SCLC: Implications for therapy. Nat Rev Clin Oncol, 2017, 14(9): 549-561.
5. Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol, 2019, 12(1): 47.
6. Shi L, Zhou Q, Wu J, et al. Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother, 2012, 61(12): 2251-2259.
7. Yu X, Zhao H, Liu L, et al. A randomized phaseⅡstudy of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol, 2014, 34(2): 194-203.
8. Brand JM, Meller B, Von Hof K, et al. Kinetics and organ distribution of allogeneic natural killer lymphocytes transfused into patients suffering from renal cell carcinoma. Stem Cells Dev, 2004, 13(3): 307-314.
9. Dai C, Lin F, Geng R, et al. Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer. Oncotarget, 2016, 7(9): 10332-10344.
10. Poh SL, Linn YC. Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. Cancer Immunol Immunother, 2016, 65(5): 525-536.
11. Bray F, Jemal A, Grey N, et al. Global cancer transitions according to the Human Development Index (2008-2030): A population-based study. Lancet Oncol, 2012, 13(8): 790-801.
12. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
13. Yang L, Wang L, Zhang Y. Immunotherapy for lung cancer: Advances and prospects. Am J Clin Exp Immunol, 2016, 5(1): 1-20.
14. Jiang J, Wu C, Lu B. Cytokine-induced killer cells promote antitumor immunity. J Transl Med, 2013, 11(1): 83.
15. Méndez R, Ruiz-Cabello F, Rodríguez T, et al. Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy. Cancer Immunol Immunother, 2007, 56(1): 88-94.
16. Wongkajornsilp A, Somchitprasert T, Butraporn R, et al. Human cytokine-induced killer cells specifically infiltrated and retarded the growth of the inoculated human cholangiocarcinoma cells in SCID mice. Cancer Invest, 2009, 27(2): 140-148.
17. Thanendrarajan S, Nowak M, Abken H, et al. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: More than one plus one? Leuk Res, 2011, 35(9): 1136-1142.
18. Schmidt-Wolf IG, Negrin RS, Kiem HP, et al. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med, 1991, 174(1): 139-149.
19. Linn YC, Wang SM, Hui KM. Comparative gene expression profiling of cytokine-induced killer cells in response to acute myloid leukemic and acute lymphoblastic leukemic stimulators using oligonucleotide arrays. Exp Hematol, 2005, 33(6): 671-681.
20. Remark R, Becker C, Gomez JE, et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med, 2015, 191(4): 377-390.
21. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 2016, 375(18): 1767-1778.
22. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection J. Nature, 2006, 439(7077): 682-687.
23. Misra P, Singh S. Role of cytokines in combinatorial immunotherapeutics of non‐small cell lung cancer through systems perspective. Cancer Med-US, 2019, 8(5): 1976-1995.
24. Yuan M, Huang LL, Chen JH, et al. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther, 2019, 4(1): 1-14.
25. Ding X, Cao H, Chen X, et al. Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer. J Transl Med, 2015, 13(1): 158.
26. Ma W, Gilligan BM, Yuan J, et al. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hemato Oncol, 2016, 9(1): 47.
27. Qin A, Coffey DG, Warren EH, et al. Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer. Cancer Med-US, 2016, 5(9): 2567-2578.
28. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol, 2004, 22: 329-360.
29. Sui X, Ma J, Han W, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget, 2015, 6(23): 19393-19404.
30. Teng F, Meng X, Kong L, et al. Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. Cancer Lett, 2018, 414: 166-173.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Influence of PD-1 monoclonal antibody on anti-lung cancer effect of cytokine-induced killer cells (CIK) induced and expanded in vitro

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