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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

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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.

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Acknowledgements

We would like to thank the volunteers who participated in this study. The authors are thankful to the coordinator of ISLS, BHU for providing the instrumental facilities. This work was carried out by the grant from the Banaras Hindu University and the University of Grant Commission, Government of India to Prof. Arbind Acharya.

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Authors and Affiliations

  1. Laboratory of Cancer Immunology, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India

    Munendra Singh Tomar, Rishi Kant Singh & Arbind Acharya

  2. Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, 119991, Russia

    Ilya V. Ulasov

  3. Department of Zoology, Pachhunga University College Campus, Mizoram University, Aizawl, 796001, India

    Kaushalendra

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  1. Munendra Singh Tomar
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Contributions

The experiments of this investigation were designed by MST and AA. MST has performed the experiments. RKS prepared reagents and helped during experiments. The manuscript was written by MST and critically reviewed by RKS, IVU, and AA. Kaushalendra helped during revision and, all authors read the final manuscript and approved it for submission.

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Correspondence to Arbind Acharya.

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Conflict of interest

This research is the part of PhD work of MST. PI had received financial support from UGC, New Delhi, and DST New Delhi. All other co-authors have contributed in performing the experimental design, writing, and critically reviewing the manuscript. On behalf of all the authors, it is declared that there is no any potential conflict of interest and all have given their consent for the publication of the manuscript.

Ethical statement

All animal experiments were performed according to the guidelines given by Institution Animal Ethical Committee (IAEC), Department of Zoology, Banaras Hindu University, Varanasi, India.

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Tomar, M.S., Singh, R.K., Ulasov, I.V. et al. 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. Cancer Immunol Immunother 72, 1429–1444 (2023). https://doi.org/10.1007/s00262-022-03339-6

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