Application of natural killer cell-based immunotherapy in lung cancer treatment

Abstract

Lung cancer is a malignant tumor originating in the bronchi, trachea, or other lung tissues. Despite significant advances in treatment, clinical outcomes remain unsatisfactory due to factors such as chemotherapy and heterogeneity. Natural killer (NK) cells are a key component of the innate immune system. A reduction in NK cell number or dysfunction can lead to immune evasion by tumor cells, contributing to malignant progression. In lung cancer, NK cell imbalance is closely associated with tumor immune escape mechanisms, making the modulation of NK cell activity a promising therapeutic strategy. This review examines the role of NK cell dysfunction in lung cancer immune escape and highlights recent advances in NK cell-based immunotherapy. Therapeutic approaches include cell-based NK therapies, cytokine stimulation, immune checkpoint inhibitors, monoclonal antibodies mediating antibody-dependent cell-mediated cytotoxicity, signal pathway-targeted agents, and bioactive compounds derived from medicinal and edible plants. Furthermore, emerging clinical evidence demonstrates the effectiveness of NK cell immunotherapy in improving treatment outcomes in lung cancer patients. This article aims to provide a comprehensive overview of current strategies to enhance NK cell function and presents novel therapeutic avenues to support future lung cancer interventions.

Keywords

Natural killer cells / Immunotherapy / Lung cancer

Funding

The work was supported by the Natural Science Foundation of China (Grant No.: 82305331), the Science and Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No.: 2022KJ180), and the “Inheritance Plan” Reserve Talent Project of the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine.

Conflict of interest

Xianbin Kong is an Editorial Board Member of this journal and Guest Editor of this special issue. The authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper

References

[1] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74(1):12-49. doi: 10.3322/caac.21830

[2] Petty WJ, Paz-Ares L. Emerging strategies for the treatment of small cell lung cancer: A review. JAMA Oncol. 2023; 9(3):419-429. doi: 10.1001/jamaoncol.2022.5631

[3] Pich O, Bailey C, Watkins TBK, Zaccaria S, Jamal- Hanjani M, Swanton C. The translational challenges of precision oncology. Cancer Cell. 2022; 40(5):458-478. doi: 10.1016/j.ccell.2022.04.002

[4] Abolfathi H, Arabi M, Sheikhpour M. A literature review of microRNA and gene signaling pathways involved in the apoptosis pathway of lung cancer. Respir Res. 2023; 24(1):55. doi: 10.1186/s12931-023-02366-w

[5] Liguori NR, Sanchez Sevilla Uruchurtu A, Zhang L, et al. Preclinical studies with ONC201/TIC10 and lurbinectedin as a novel combination therapy in small cell lung cancer (SCLC). Am J Cancer Res. 2022; 12(2):729-743.

[6] Liu Y, Tian S, Ning B, Huang T, Li Y, Wei Y. Stress and cancer: The mechanisms of immune dysregulation and management. Front Immunol. 2022; 13:1032294. doi: 10.3389/fimmu.2022.1032294

[7] Chen D, Zhang X, Li Z, Zhu B. Metabolic regulatory crosstalk between tumor microenvironment and tumor-associated macrophages. Theranostics. 2021; 11(3):1016-1030. doi: 10.7150/thno.51777

[8] van Weverwijk A, de Visser KE. Mechanisms driving the immunoregulatory function of cancer cells. Nat Rev Cancer. 2023; 23(4):193-215. doi: 10.1038/s41568-022-00544-4

[9] Russell É, Conroy MJ, Barr MP. Harnessing natural killer cells in non-small cell lung cancer. Cells. 2022; 11(4):605. doi: 10.3390/cells11040605

[10] Guo Y, Liu Y, Rui B, et al. Crosstalk between the gut microbiota and innate lymphoid cells in intestinal mucosal immunity. Front Immunol. 2023; 14:1171680. doi: 10.3389/fimmu.2023.1171680

[11] Vyas M, Requesens M, Nguyen TH, Peigney D, Azin M, Demehri S. Natural killer cells suppress cancer metastasis by eliminating circulating cancer cells. Front Immunol. 2023; 13:1098445. doi: 10.3389/fimmu.2022.1098445

[12] Pockley AG, Vaupel P, Multhoff G. NK cell-based therapeutics for lung cancer. Expert Opin Biol Ther. 2020; 20(1):23-33. doi: 10.1080/14712598.2020.1688298

[13] Stabile H, Fionda C, Gismondi A, et al. Role of distinct natural killer cell subsets in anticancer response. Front Immunol. 2017; 8:293. doi: 10.3389/fimmu.2017.00293

[14] Liu S, Galat V, Galat Y, et al. NK cell-based cancer immunotherapy: From basic biology to clinical development. J Hematol Oncol. 2021; 14(1):7. doi: 10.1186/s13045-020-01014-w

[15] Lee H, Da Silva IP, Palendira U, Scolyer RA, Long GV, Wilmott JS. Targeting NK cells to enhance melanoma response to immunotherapies. Cancers (Basel). 2021; 13(6):1363. doi: 10.3390/cancers13061363

[16] Li Y, Orange JS. Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis. PLoS Biol. 2021; 19(8):e3001328. doi: 10.1371/journal.pbio.3001328

[17] Zeng Y, Lv X, Du J. Natural killer cell-based immunotherapy for lung cancer: Challenges and perspectives (review). Oncol Rep. 2021; 46(5):232. doi: 10.3892/or.2021.8183

[18] Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020; 19(1):120. doi: 10.1186/s12943-020-01238-x

[19] Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-γ in tumor progression and regression: A review. Biomark Res. 2020; 8:49. doi: 10.1186/s40364-020-00228-x

[20] Manohar SM. At the crossroads of TNF α signaling and cancer. Curr Mol Pharmacol. 2024; 17(1):e060923220758. doi: 10.2174/1874467217666230908111754

[21] Tuomela K, Ambrose AR, Davis DM. Escaping death: How cancer cells and infected cells resist cell-mediated cytotoxicity. Front Immunol. 2022; 13:867098. doi: 10.3389/fimmu.2022.867098

[22] Meng F, Zhang S, Xie J, et al. Leveraging CD16 fusion receptors to remodel the immune response for enhancing anti-tumor immunotherapy in iPSC-derived NK cells. J Hematol Oncol. 2023; 16(1):62. doi: 10.1186/s13045-023-01455-z

[23] Guillerey C. NK cells in the tumor microenvironment. Adv Exp Med Biol. 2020; 1273:69-90. doi: 10.1007/978-3-030-49270-0_4

[24] Hodge G, Barnawi J, Jurisevic C, et al. Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells. Clin Exp Immunol. 2014; 178(1):79-85. doi: 10.1111/cei.12392

[25] Schmidt L, Eskiocak B, Kohn R, et al. Enhanced adaptive immune responses in lung adenocarcinoma through natural killer cell stimulation. Proc Natl Acad Sci USA. 2019; 116(35):17460-17469. doi: 10.1073/pnas.1904253116

[26] Lee JC, Lee KM, Kim DW, et al. Elevated TGF- β1secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004; 172(12):7335-7340. doi: 10.4049/jimmunol.172.12.7335

[27] Hodgins JJ, Khan ST, Park MM, Auer RC, Ardolino M. Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Invest. 2019; 129(9):3499-3510. doi: 10.1172/JCI129338

[28] Xu L, Zheng Y, Wang J, Xu Y, Xie Y, Yang ZP. IL33 activates CD8+ T andNK cells through MyD88 pathway to suppress the lung cancer cell growth in mice. Biotechnol Lett. 2020; 42(7):1113-1121. doi: 10.1007/s10529-020-02815-2

[29] Niu C, Li M, Zhu S, et al. PD-1-positive natural killer cells have a weaker antitumor function than that of PD-1- negative natural killer cells in lung cancer. Int J Med Sci. 2020; 17(13):1964-1973. doi: 10.7150/ijms.47701

[30] Terrén I, Orrantia A, Vitallé J, Zenarruzabeitia O, Borrego F. NK cell metabolism and tumor microenvironment. Front Immunol. 2019; 10:2278. doi: 10.3389/fimmu.2019.02278

[31] Donnelly RP, Loftus RM, Keating SE, et al. mTORC1- dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol. 2014; 193(9):4477-4484. doi: 10.4049/jimmunol.1401558

[32] Cong J, Wang X, Zheng X, et al. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab. 2018; 28(2):243-255. doi: 10.1016/j.cmet.2018.06.021

[33] Platonova S, Cherfils-Vicini J, Damotte D, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 2011; 71(16):5412-5422. doi: 10.1158/0008-5472.CAN-10-4179

[34] Zhang P, He B, Cai Q, et al. Decreased IL-6 and NK cells in early-stage lung adenocarcinoma presenting as ground glass opacity. Front Oncol. 2021; 11:705888. doi: 10.3389/fonc.2021.705888

[35] Frese-Schaper M, Keil A, Yagita H, et al. Influence of natural killer cells and perforin-mediated cytolysis on the development of chemically induced lung cancer in A/J mice. Cancer Immunol Immunother. 2014; 63(6):571-580. doi: 10.1007/s00262-014-1535-x

[36] Pan C, Zhai Y, Li G, Jiang T, Zhang W. NK cell-based immunotherapy and therapeutic perspective in gliomas. Front Oncol. 2021; 11:751183. doi: 10.3389/fonc.2021.751183

[37] Zhang J, Zheng H, Diao Y. Natural killer cells and current applications of chimeric antigen receptor-modified NK-92cells in tumor immunotherapy. Int J Mol Sci. 2019; 20(2):317. doi: 10.3390/ijms20020317

[38] Ames E, Murphy WJ. Advantages and clinical applications of natural killer cells in cancer immunotherapy. Cancer Immunol Immunother. 2014; 63(1):21-28. doi: 10.1007/s00262-013-1469-8

[39] Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR-NK cells: A promising cellular immunotherapy for cancer. EBioMedicine. 2020; 59:102975. doi: 10.1016/j.ebiom.2020.102975

[40] Yang S, Cao B, Zhou G, et al. Targeting B7-H3 immune checkpoint with chimeric antigen receptor-engineered natural killer cells exhibits potent cytotoxicity against non-small cell lung cancer. Front Pharmacol. 2020; 11:1089. doi: 10.3389/fphar.2020.01089

[41] Marofi F, Al-Awad AS, Sulaiman Rahman H, et al. CAR NK cell: A new paradigm in tumor immunotherapy. Front Oncol. 2021; 11:673276. doi: 10.3389/fonc.2021.673276

[42] Lin M, Luo H, Liang S, et al. Pembrolizumab plus allogeneic NK cells in advanced non-small cell lung cancer patients. J Clin Invest. 2020; 130(5):2560-2569. doi: 10.1172/JCI132712

[43] Iliopoulou EG, Kountourakis P, Karamouzis MV, et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother. 2010; 59(12):1781-1789. doi: 10.1007/s00262-010-0904-3

[44] Hellstrand K, Hermodsson S, Naredi P, Mellqvist UH, Brune M. Histamine and cytokine therapy: Paper presented at the annual meeting of the Swedish Oncology Society, Stockholm, 1997. Acta Oncol. 1998; 37(4):347-353. doi: 10.1080/028418698430566

[45] Bates AM, Brown RJ, Pieper AA, et al. Combination of bempegaldesleukin and anti-CTLA-4 prevents metastatic dissemination after primary resection or radiotherapy in a preclinical model of non-small cell lung cancer. Front Oncol. 2021; 11:645352. doi: 10.3389/fonc.2021.645352.

[46] Desbois M, Béal C, Charrier M, et al. IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: Implications for antimetastatic treatment. J Immunother Cancer. 2020; 8(1):e000632. doi: 10.1136/jitc-2020-000632

[47] Marin-Acevedo JA, Kimbrough EMO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol. 2021; 14(1):45. doi: 10.1186/s13045-021-01056-8

[48] Jain P, Jain C, Velcheti V. Role of immune-checkpoint inhibitors in lung cancer. Ther Adv Respir Dis. 2018; 12:175346581775007. doi: 10.1177/1753465817750075

[49] Trefny MP, Kaiser M, Stanczak MA, et al. PD-1+ natural killer cells in human non-small cell lung cancer can be activated by PD-1/PD-L1 blockade. Cancer Immunol Immunother. 2020; 69(8):1505-1517. doi: 10.1007/s00262-020-02558-z

[50] Leonetti A, Wever B, Mazzaschi G, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist Update. 2019; 46:100644. doi: 10.1016/j.drup.2019.100644

[51] Li Y, Zhang Y, Cao G, et al. Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors. J Hematol Oncol. 2021; 14(1):100. doi: 10.1186/s13045-021-01112-3

[52] Qu YH, Li Y. Progress of study on antitumor effects of antibody dependent cell mediated cytotoxicity-review. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010; 18(5):1370-1375.

[53] Kurai J, Chikumi H, Hashimoto K, et al. Antibody dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 2007; 13(5):1552-1561. doi: 10.1158/1078-0432.CCR-06-1726

[54] Minami T, Kijima T, Otani Y, et al. HER2 as therapeutic target for overcoming ATP-binding cassette transporter-mediated chemoresistance in small cell lung cancer. Mol Cancer Ther. 2012; 11(4):830-841. doi: 10.1158/1535-7163.MCT-11-0884

[55] Imyanitov EN, Iyevleva AG, Levchenko EV. Molecular testing and targeted therapy for non-small cell lung cancer: Current status and perspectives. Crit Rev Oncol Hematol. 2021; 157:103194. doi: 10.1016/j.critrevonc.2020.103194

[56] Pujol JL, Vansteenkiste J, Paz-Ares Rodríguez L, et al. Abemaciclib in combination with pembrolizumab for stage IV KRAS-mutant or squamous NSCLC: A phase 1b study. JTO Clin Res Rep. 2021; 2(11):100234. doi: 10.1016/j.jtocrr.2021.100234

[57] Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011; 29(15):2046-2051. doi: 10.1200/JCO.2010.33.1280

[58] Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: New rational therapeutic strategies for actionable mutations. Oncogene. 2018; 37(24):3183-3199. doi: 10.1038/s41388-018-0171-x

[59] Daga A, Ansari A, Patel S, et al. Current drugs and drug targets in non-small cell lung cancer: Limitations and opportunities. Asian Pac J Cancer Prev. 2015; 16(10):4147-4156. doi: 10.7314/apjcp.2015.16.10.4147

[60] Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014; 371(23):2167-2177. doi: 10.1056/NEJMoa1408440

[61] He J, Yin P, Xu K. Effect and molecular mechanisms of traditional Chinese medicine on tumor targeting tumor associated macrophages. Drug Des Devel Ther. 2020; 14:907-919. doi: 10.2147/DDDT.S223646

[62] Liu JC, Narva S, Zhou K, Zhang W. A review on the antitumor activity of various nitrogenous-based heterocyclic com pounds as NSCLC inhibitors. Mini Rev Med Chem. 2019; 19(18):1517-1530. doi: 10.2174/1389557519666190312152358

[63] Yao C, Ni Z, Gong C, et al. Rocaglamide enhances NK cell-mediated killing of non-small cell lung cancer cells by inhibiting autophagy. Autophagy. 2018; 14(10):1831-1844. doi: 10.1080/15548627.2018.1489946

[64] Yao JL, Fang SM, Liu R, et al. A review on the terpenes from genus vitex. Molecules. 2016; 21(9):1179. doi: 10.3390/molecules21091179

[65] Lian GY, Wang QM, Tang PMK, Zhou S, Huang XR, Lan HY. Combination of Asiatic acid and naringenin modulates NK cell anti-cancer immunity by rebalancing Smad3/Smad7 signaling. Mol Ther. 2018; 26(9):2255-2266. doi: 10.1016/j.ymthe.2018.06.016

[66] Gong C, Yao C, Xu Z, et al. Enhancement of NK cell mediated lysis of non-small lung cancer cells by nPK Cactivator, ingenol 3,20 dibenzoate. Mol Immunol. 2017; 83:23-32. doi: 10.1016/j.molimm.2017.01.012

[67] Dimitroulis J, Rapti A, Stathopoulos GP, et al. Comparison of cisplatin-paclitaxel combination versus cisplatin-etoposidein patients with small-cell lung cancer: A phase III study. Oncol Rep. 1994; 20(4):879-884.

[68] Gupta N, Hatoum H, Dy GK. First line treatment of advanced non-small-cell lung cancer-specific focus on albumin bound paclitaxel. Int J Nanomed. 2014; 9:209-21. doi: 10.2147/IJN.S41770

[69] Liew MS, Sia J, Starmans MHW, et al. Comparison of toxicity and outcomes of concurrent radiotherapy with carboplatin/ paclitaxel or cisplatin/etoposide in stage III non-small cell lung cancer. Cancer Med. 2013; 2(6):916-924. doi: 10.1002/cam4.142

[70] Yue T, Zheng X, Dou Y, et al. Interleukin 12 shows a better curative effect on lung cancer than paclitaxel and cisplatin doublet chemotherapy. BMC Cancer. 2016; 16(1):665. doi: 10.1186/s12885-016-2701-7

[71] Khater M, Ravishankar D, Greco F, Osborn HM. Metal complexes of flavonoids: Their synthesis, characterization and enhanced antioxidant and anticancer activities. Future Med Chem. 2019; 11(21):2845-2867. doi: 10.4155/fmc-2019-0237

[72] Sun Y, Gong C, Ni Z, et al. Tanshinone IIA enhances susceptibility of non-small cell lung cancer cells to NK cell-mediated lysis by up-regulating ULBP1 and DR5. J Leukoc Biol. 2021; 110(2):315-325. doi: 10.1002/JLB.5MA1120-776RR

[73] Chen RL, Wang Z, Huang P, et al. Isovitexin potentiated the antitumor activity of cisplatin by inhibiting the glucose metabolism of lung cancer cells and reduced cisplatin induced immunotoxicity in mice. Int Immunopharmacol. 2021; 94:107357. doi: 10.1016/j.intimp.2020.107357

[74] Zeng P, Li J, Chen Y, Zhang L. The structures and biological functions of polysaccharides from traditional Chinese herbs. Prog Mol Biol Transl Sci. 2019; 163:423-444.doi: 10.1016/bs.pmbts.2019.03.003

[75] Maity P, Sen IK, Chakraborty I, et al. Biologically active polysaccharide from edible mushrooms: A review. Int J Biol Macromol. 2021; 172:408-417. doi: 10.1016/j.ijbiomac.2021.01.081

[76] Wang Y, An EK, Kim SJ, You SG, Jin JO. Intranasal administration of codium fragile polysaccharide elicits anti-cancer immunity against lewis lung carcinoma. Int J Mol Sci. 2021; 22(19):10608. doi: 10.3390/ijms221910608

[77] Wang Y, Huang M, Sun R, Pan L. Extraction, characterization of a Ginseng fruits polysaccharide and its immune modulating activities in rats with lewis lung carcinoma. Carbohydr Polym. 2015; 127:215-221. doi: 10.1016/j.carbpol.2015.03.070

[78] Lemieszek MK, Nunes FM, Rzeski W. Branched mannans from the mushroom Cantharellus cibarius enhance the anticancer activity of natural killer cells against human cancers of lung and colon. Food Funct. 2019; 10(9):5816-5826. doi: 10.1039/c9fo00510b

[79] Kwak BS, Hwang D, Lee SJ, Choi HJ, Park HY, Shin KS. Rhamnogalacturonan I-type polysaccharide purified from broccoli exerts anti metastatic activities via innate immune cell activation. J Med Food. 2019; 22(5):451-459. doi: 10.1089/jmf.2018.4286

[80] Jin Y, Yang Q, Liang L, et al. Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway. J Exp ClinCancer Res. 2018; 37(1):277. doi: 10.1186/s13046-018-0948-3

[81] Jin Y, Cai L, Yang Q, et al. Anti-leukemia activities of selenium nanoparticles embedded in nanotube consisted of triple-helix β-d-glucan. Carbohydr Polym. 2020; 240:116329. doi: 10.1016/j.carbpol.2020.116329

[82] Luo Y, Wu J, Zhu X, et al. NK cell-dependent growth inhibition of lewis lung cancer by Yu-Ping-Feng, an ancient Chinese herbal formula. Mediators Inflamm. 2016; 2016:354128. doi: 10.1155/2016/3541283

[83] LI CC, Chen MM, Zou W, et al. Application and research progress of immunotherapy based on NK cells in cancer treatment. Chin J Biol Sci. 2019, 56(12):1-4.

[84] Li M, Li SM, Yu Y, et al. Natural killer cell-related microenvironment and immunotherapy in lung cancer. Med Rev. 2019, 27(1):100-104.

[85] Ren WW. Systematic Review and Meta-analysis of Biological Immunotherapy for Non-small Cell Lung Cancer. China: Lanzhou University; 2014.

[86] Wang CJ, Yang LL, Li ZY, et al. The application of NK cells in the comprehensive treatment of advanced colon cancer. Chin Modern Doctor. 2019, 57(14):72-76+80+169.

[87] Lu SH. Clinical Observation of Autologous T Cell Immunotherapy Combined with Chemotherapy in the Treatment of Advanced non-small Cell Lung Cancer. China Guangxi Medical University; 2013.

[88] Cao H. Clinical Efficacy Analysis of Cell Immunotherapy Combined with Chemotherapy in the Treatment of Small Cell Lung Cancer. China: Jilin University; 2014.

[89] Yin ZC. Clinical Efficacy Analysis of Cellular Immunotherapy Combined with Chemotherapy in the Treatment of Recurrent Ovarian Cancer. China: Jilin University; 2015.

[90] Xie LY. Efficacy and Safety Analysis of Cellular Immunotherapy Combined with Chemotherapy in the Treatment of Colorectal Cancer. China: Jilin University; 2019.

[91] Sun HY. The Role of Alloreactive NK Cells in the Treatment of Lung Cancer by Mouse Haploid Bone Marrow Transplantation. China: Tianjin Medical University; 2010.

[92] Li JY. In Vitro Experimental Study of NK and T Mixed Lymphocytes Combined with Cisplatin or Cetuximab in NSCLC. China: PLA Military Medical College; 2010.