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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 6/2023

03-12-2022 | Lymphoma | Research

Refurbishment of NK cell effector functions through their receptors by depleting the activity of nTreg cells in Dalton’s Lymphoma-induced tumor microenvironment: an in vitro and in vivo study

Authors: Munendra Singh Tomar, Rishi Kant Singh, Ilya V. Ulasov, Kaushalendra, Arbind Acharya

Published in: Cancer Immunology, Immunotherapy | Issue 6/2023

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Abstract

Natural killer (NK) cells play a crucial role in the anti-tumor transaction through cytolytic activity with the help of proportionate expression of their activating receptors (ARs) and inhibitory receptors (IRs). The proliferation, differentiation, and effector’s functions of NK cells were affected and regulated by CD4+CD25+ regulatory T (Treg) cells through the NKG2D receptor expressed on NK cells. It has not yet been established whether Treg cells also affects the expression and functions of other receptors of NK cell. Moreover, the effect of cyclophosphamide (CYP) treatment on the expression and functions of AR and IR receptors of NK cells regulated by Treg cells during cancer progression is not clearly understood. Therefore, we have used the metronomic dose of CYP and anti-CD25 and anti-TGF-β to inhibit the effects of Treg cells in DL-induced tumor microenvironment and analyze the expression of ARs and IRs on NK cells and the FoxP3 level on Treg cells. It was observed that treatment of CYP and blocking antibodies not only affects the functions of tumor-associated NK cells (TANK cells) by modulating the expression of ARs and IRs in DL-induced tumor microenvironment, but also downregulates the functions of Treg cells. The findings of our study supported and suggested that the use of CYP in combination with other therapeutic approaches will effectively reduce tumor growth directly and/or indirectly by modulating the NK cell-mediated immune response of the host.
Literature
1.
Vitale M et al (2014) Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol 44(6):1582–1592PubMedCrossRef
2.
Han B et al (2018) Altered NKp30, NKp46, NKG2D, and DNAM-1 expression on circulating NK cells is associated with tumor progression in human gastric cancer. J Immunol Res 2018:6248590PubMedPubMedCentralCrossRef
3.
Garcia-Iglesias T et al (2009) Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer 9:186PubMedPubMedCentralCrossRef
4.
Sandoval-Borrego D et al (2016) Overexpression of CD158 and NKG2A inhibitory receptors and underexpression of NKG2D and NKp46 activating receptors on NK cells in acute Myeloid Leukemia. Arch Med Res 47(1):55–64PubMedCrossRef
5.
6.
Wai LE et al (2011) Distinct roles for the NK cell-activating receptors in mediating interactions with dendritic cells and tumor cells. J Immunol 186(1):222–229PubMedCrossRef
7.
French AR, Yokoyama WM (2004) Natural killer cells and autoimmunity. Arthritis Res Ther 6(1):8–14PubMedCrossRef
8.
Tomar MS et al (2018) NK cell effector functions regulation by modulating nTreg cell population during progressive growth of Dalton’s lymphoma in mice. Immunol Invest 47(1):40–56PubMedCrossRef
9.
Bergmann C et al (2011) Human tumor-induced and naturally occurring Treg cells differentially affect NK cells activated by either IL-2 or target cells. Eur J Immunol 41(12):3564–3573PubMedCrossRef
10.
Ghiringhelli F et al (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202(8):1075–1085PubMedPubMedCentralCrossRef
11.
Jewett A, Man YG, Tseng HC (2013) Dual functions of natural killer cells in selection and differentiation of stem cells; role in regulation of inflammation and regeneration of tissues. J Cancer 4(1):12–24PubMedCrossRef
12.
Ralainirina N et al (2007) Control of NK cell functions by CD4+CD25+ regulatory T cells. J Leukoc Biol 81(1):144–153PubMedCrossRef
13.
14.
Attias M, Al-Aubodah T, Piccirillo CA (2019) Mechanisms of human FoxP3(+) Treg cell development and function in health and disease. Clin Exp Immunol 197(1):36–51PubMedPubMedCentralCrossRef
15.
Yun X, Shang Y, Li M (2015) Effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4(+) CD25(+) Foxp3(+) Treg in asthma Balb/c mouse. Int J Clin Exp Pathol 8(7):7661–7674PubMedPubMedCentral
16.
17.
Tongu M et al (2013) Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol Immunother 62(2):383–391PubMedCrossRef
18.
Man S et al (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62(10):2731–2735PubMed
19.
Lutsiak ME et al (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105(7):2862–2868PubMedCrossRef
20.
Ding ZC, Munn DH, Zhou G (2014) Chemotherapy-induced myeloid suppressor cells and antitumor immunity: The Janus face of chemotherapy in immunomodulation. Oncoimmunology 3(8):e954471PubMedPubMedCentralCrossRef
21.
Luznik L, Fuchs EJ (2010) High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47(1–3):65–77PubMedPubMedCentralCrossRef
22.
Ghiringhelli F et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56(5):641–648PubMedCrossRef
23.
Oh E, et al (2019) Erratum: Oh E, et al. Cryopreserved human natural killer cells exhibit potent antitumor efficacy against orthotopic pancreatic cancer through efficient tumor-homing and cytolytic ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect). Cancers 2019, 11, 966. Cancers (Basel), 2020. 12(11).
24.
25.
Sharma G et al (2017) p53 dependent apoptosis and cell cycle delay induced by heteroleptic complexes in human cervical cancer cells. Biomed Pharmacother 88:218–231PubMedCrossRef
26.
Valiathan R et al (2012) Evaluation of a flow cytometry-based assay for natural killer cell activity in clinical settings. Scand J Immunol 75(4):455–462PubMedCrossRef
27.
Lee J et al (2017) Natural killer cell activity for IFN-gamma production as a supportive diagnostic marker for gastric cancer. Oncotarget 8(41):70431–70440PubMedPubMedCentralCrossRef
28.
Tallerico R et al (2013) Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J Immunol 190(5):2381–2390PubMedCrossRef
29.
Nieto-Velazquez NG et al (2016) Altered expression of natural cytotoxicity receptors and NKG2D on peripheral blood NK cell subsets in breast cancer patients. Transl Oncol 9(5):384–391PubMedPubMedCentralCrossRef
30.
Shi L et al (2018) Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer. Proc Natl Acad Sci U S A 115(46):11808–11813PubMedPubMedCentralCrossRef
31.
Wang XJ et al (2009) Activated T cells inhibit NK cell-mediated tumour rejection. Scand J Immunol 69(4):337–341PubMedCrossRef
32.
Smyth MJ et al (2004) NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 200(10):1325–1335PubMedPubMedCentralCrossRef
33.
Salcedo M et al (1997) Altered expression of Ly49 inhibitory receptors on natural killer cells from MHC class I-deficient mice. J Immunol 158(7):3174–3180PubMedCrossRef
34.
35.
Vahlne G et al (2008) IFN-gamma production and degranulation are differentially regulated in response to stimulation in murine natural killer cells. Scand J Immunol 67(1):1–11PubMed
36.
37.
38.
Feng PH et al (2020) NKG2D-Fc fusion protein promotes antitumor immunity through the depletion of immunosuppressive cells. Cancer Immunol Immunother 69(10):2147–2155PubMedPubMedCentralCrossRef
39.
40.
Scurr M et al (2017) Low-dose cyclophosphamide induces antitumor T-cell responses, which associate with survival in metastatic colorectal cancer. Clin Cancer Res 23(22):6771–6780PubMedPubMedCentralCrossRef
41.
Huijts CM et al (2019) The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial. Cancer Immunol Immunother 68(3):503–515PubMedPubMedCentralCrossRef
42.
Geng X et al (2019) CD4+CD25+Foxp3+ regulatory T cells suppress NKG2D-mediated NK cell cytotoxicity in peripheral blood. Medicine (Baltimore) 98(22):e15722PubMedCrossRef
43.
44.
Moretta A et al (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223PubMedCrossRef
Metadata
Title
Refurbishment of NK cell effector functions through their receptors by depleting the activity of nTreg cells in Dalton’s Lymphoma-induced tumor microenvironment: an in vitro and in vivo study
Authors
Munendra Singh Tomar
Rishi Kant Singh
Ilya V. Ulasov
Kaushalendra
Arbind Acharya
Publication date
03-12-2022
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 6/2023
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-022-03339-6

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