Vojnosanitetski pregled 2022 Volume 79, Issue 8, Pages: 764-773
https://doi.org/10.2298/VSP210126039J
Full text (
1436 KB)
Cited by
Anti-PD-1 therapy activates tumoricidic properties of NKT cells and contributes to the overall deceleration of tumor progression in a model of murine mammary carcinoma
Jovanović Marina (University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia)
Gajović Nevena (University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia)
Jurišević Milena (University of Kragujevac, Faculty of Medical Sciences, Department of Pharmacy, Kragujevac, Serbia)
Sekulić Sofija 
(University of Kragujevac, Faculty of Medical Sciences, Department of Infectious Diseases, Kragujevac, Serbia)
Arsenijević Nebojša (University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia)
Jocić Miodrag (Military Medical Academy, Institute for Transfusiology and Haemobiology, Belgrade, Serbia), jocicmiodrag@gmail.com
Jovanović Milan (Military Medical Academy, Clinic for Abdominal Surgery, Belgrade, Serbia)
Lukić Ružica (Military Medical Academy, University of East Sarajevo, Faculty of Medicine, Department of Microbiology, Foča, Bosnia and Herzegovina)
Jovanović Ivan (University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia)
Radovanović Dragče (University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia)
Background/Aim. Immune checkpoint therapy is a well-established therapeutic approach in the treatment of malignant diseases and is thought to be mostly based on facilitating the adaptive immune response. However, the cells of the innate immune response, such as natural killer T (NKT) cells, might also be important for a successful anti-programmed cell death protein-1 (anti-PD-1) therapy, as they initiate the antitumor immune response. The aim of this study was to investigate the influence of anti-PD-1 therapy on the immune response against tumors. Methods. For tumor induction, 4T1 cells synergic to BALB/c back-ground were used, after which mice underwent anti-PD-1 treatment. After the mice were sacrificed, NKT cells, dendritic cells (DCs), and macrophages derived from spleen and primary tumor tissue were analyzed using flow cytometry. Results. Anti-PD-1 therapy enhanced the expression of activating molecules CD69, NKp46, and NKG2D in NKT cells of the tumor and spleen. This therapy activated NKT cells directly and indirectly via DCs. Activated NKT cells acquired tumoricidic properties directly, by secreting perforin, and indirectly by stimulating M1 macrophages polarization. Conclusion. Anti-PD-1 therapy activates changes in DCs and macrophages of primary tumor tissue towards protumoricidic activity. Since anti-PD-1 therapy induces significant changes in NKT cells, DCs, and macrophages, the efficacy of the overall antitumor response is increased and has significantly decelerated tumor growth.
Keywords: antineoplastic agents, breast neoplasms, immunomodulation, killer cell, natural, macrophages, mice
Show references
Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med 2016; 14: 73.
Li B, Chan HL, Chen P. Immune Checkpoint Inhibitors: Basics and Challenges. Curr Med Chem 2019; 26(17): 3009-25.
Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol 2017; 8: 561.
Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: A growing relationship. Cell Immunol 2016; 310: 27-41.
Habib S, El Andaloussi A, Elmasry K, Handoussa A, Azab M, Elsawey A, et al. PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmaniadonovani. Infect Immun 2018; 86(6): e00019-18.
Mazzaschi G, Facchinetti F, Missale G, Canetti D, Madeddu D, Zecca A, et al. The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC. Lung Cancer 2019; 127: 153-63.
Oyer JL, Gitto SB, Altomare DA, Copik AJ. PD-L1 blockade enhances anti-tumor efficacy of NK cells. Oncoimmunology 2018; 7(11): e1509819.
Patel SP, Kurzrock R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther 2015; 14(4): 847-56.
Rouanne M, Roumiguié M, Houédé N, Masson-Lecomte A, Colin P, Pignot G, et al. Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways. World J Urol 2018; 36(11): 1727-40.
Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother 2016; 12(11): 2777-89.
Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers (Basel) 2020; 12(3): 738.
Dong W, Wu X, Ma S, Wang Y, Nalin AP, Zhu Z, et al. The Mechanism of Anti-PD-L1 Antibody Efficacy against PD-L1-Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector. Cancer Discov 2019; 9(10): 1422-37.
Zhang C, Liu Y. Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy. Front Immunol 2020; 11: 1295.
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol 2015; 194(3): 950-9.
Exley MA, Wilson SB, Balk SP. Isolation and Functional Use of Human NKT Cells. Curr Protoc Immunol 2017; 119: 14.11.1-14.11.20.
Qin L, Dominguez D, Chen S, Fan J, Long A, Zhang M, et al. Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia. Oncotarget 2016; 7(38): 61069-80.
Shimizu T, Fuchimoto Y, Fukuda K, Okita H, Kitagawa Y, Kuroda T. The effect of immune checkpoint inhibitors on lung metastases of osteosarcoma. J Pediatr Surg 2017; 52(12): 2047-50.
Vo MC, Jung SH, Chu TH, Lee HJ, Lakshmi TJ, Park HS, et al. Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma. Front Immunol 2018; 9: 1370.
Jovanovic I, Radosavljevic G, Mitrovic M, Juranic VL, McKenzie AN, Arsenijevic N, et al. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma. Eur J Immunol 2011; 41(7): 1902-12.
Taniguchi M, Harada M, Dashtsoodol N, Kojo S. Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy. Proc Jpn Acad Ser B Phys Biol Sci 2015; 91(7): 292-304.
Ribeiro Gomes J, Schmerling RA, Haddad CK, Racy DJ, Ferrigno R, Gil E, et al. Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic Solid Tumors. J Immunother 2016; 39(9): 367-72.
Khan M, Lin J, Liao G, Tian Y, Liang Y, Li R, et al. Comparative analysis of immune checkpoint inhibitors and chemotherapy in the treatment of advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97(33): e11936.
Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, et al. Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers. PLoS One 2015; 10(6): e0130142.
Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017; 24(1): 26.
Ngiow SF, Young A, Jacquelot N, Yamazaki T, Enot D, Zitvogel L, et al. A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1. Cancer Res 2015; 75(18): 3800-11.
Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity 2018; 48(3): 434-52.
Antonia SJ, Vansteenkiste JF, Moon E. Immunotherapy: Beyond Anti-PD-1 and Anti-PD-L1 Therapies. Am Soc Clin Oncol Educ Book 2016; 35: e450-8.
Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 2017; 355(6332): 1428-33.
Kagamu H, Kitano S, Yamaguchi O, Yoshimura K, Horimoto K, Kitazawa M, et al. CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy. Cancer Immunol Res 2020; 8(3): 334-44.
Bae EA, Seo H, Kim BS, Choi J, Jeon I, Shin KS, et al. Activation of NKT Cells in an Anti-PD-1-Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells. Cancer Res 2018; 78(18): 5315-26.
Terabe M, Berzofsky JA. Tissue-Specific Roles of NKT Cells in Tumor Immunity. Front Immunol 2018; 9: 1838.
Tiwary S, Berzofsky JA, Terabe M. Altered Lipid Tumor Environment and Its Potential Effects on NKT Cell Function in Tumor Immunity. Front Immunol 2019; 10: 2187.
Kim N, Kim HS. Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells. Front Immunol 2018; 9: 2041.
Teyton L. New Directions for Natural Killer T Cells in the Immunotherapy of Cancer. Front Immunol 2017; 8: 1480.
Sivori S, Pende D, Quatrini L, Pietra G, Della Chiesa M, Vacca P, et al. NK cells and ILCs in tumor immunotherapy. Mol Aspects Med 2020; 100870.
Theodoraki MN, Yerneni SS, Hoffmann TK, Gooding WE, Whiteside TL. Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients. Clin Cancer Res 2018; 24(4): 896-905.
Xue W, Li W, Zhang T, Li Z, Wang Y, Qiu Y, et al. Anti-PD1 upregulates PD-L1 expression and inhibits T-cell lymphoma progression: possible involvement of an IFN-γ-associated JAK-STAT pathway. Onco Targets Ther 2019; 12: 2079-88.
Qin Y, Oh S, Lim S, Shin JH, Yoon MS, Park SH. Invariant NKT cells facilitate cytotoxic T-cell activation via direct recognition of CD1d on T cells. Exp Mol Med 2019; 51(10): 1-9.
Krijgsman D, Hokland M, Kuppen PJK. The role of natural killer T cells in cancer-A phenotypical and functional approach. Front Immunol 2018; 9: 367.
Bedard M, Salio M, Cerundolo V. Harnessing the power of invariant natural killer T cells in cancer immunotherapy. Front Immunol 2017; 8: 1829.
Díaz-Basabe A, Strati F, Facciotti F. License to Kill: When iNKT Cells Are Granted the Use of Lethal Cytotoxicity. Int J Mol Sci 2020; 21(11): 3909.
Fallarini S, Paoletti T, Orsi Battaglini N, Lombardi G. Invariant NKT cells increase drug-induced osteosarcoma cell death. Br J Pharmacol 2012; 167(7): 1533-49.
Hix LM, Shi YH, Brutkiewicz RR, Stein PL, Wang CR, Zhang M. CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis. PLoS One 2011; 6(6): e20702.
Tan B, Shi X, Zhang J, Qin J, Zhang N, Ren H, et al. Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization. Cancer Res 2018; 78(17): 4929-42.
Xiang W, Shi R, Kang X, Zhang X, Chen P, Zhang L, et al. Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression. Nat Commun 2018; 9(1): 2574.
Najafi M, Hashemi Goradel N, Farhood B, Salehi E, Nashtaei MS, Khanlarkhani N, et al. Macrophage polarity in cancer: A review. J Cell Biochem 2019; 120(3): 2756-65.
Li TF, Li K, Wang C, Liu X, Wen Y, Xu YH, et al. Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment. J Control Release 2017; 268: 128-46.
Donzelli S, Milano E, Pruszko M, Sacconi A, Masciarelli S, Iosue I, et al. Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages. Breast Cancer Res 2018; 20(1): 59.
Sumpter TL, Dangi A, Matta BM, Huang C, Stolz DB, Vodovotz Y, et al. Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO. J Immunol 2012; 189(8): 3848-58.
Motta JM, Rumjanek VM. Sensitivity of Dendritic Cells to Microenvironment Signals. J Immunol Res 2016; 2016: 4753607.
Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations. Int Rev Cell Mol Biol 2019; 348: 1-68.
Fujii SI, Shimizu K. Exploiting Antitumor Immunotherapeutic Novel Strategies by Deciphering the Cross Talk between Invariant NKT Cells and Dendritic Cells. Front Immunol 2017; 8: 886.
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018; 233(9): 6425-40.