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Gene & Protein in Disease

PERSPECTIVE ARTICLE
Combination cancer therapy integrating T-cell

immune checkpoint blockers and natural killer
cell activation

Junyi Li and Yanzhang Wei*

Department of Biological Sciences, College of Science, Clemson University, Clemson,
South Carolina, United States of America

Abstract

T-cell immune checkpoint blockers (ICBs) and natural killer (NK) cell activation
have emerged as promising strategies for cancer therapy in recent years. In this
approach, ICBs target inhibitory receptors on cytotoxic immune cells, such as
programmed death Protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), to
enhance immune cell cytotoxicity against cancer cells in a CD8 T cell-dependent
+
manner. Meanwhile, NK cells play a critical role in immunosurveillance through their
direct cytotoxic effects, which do not require prior activation. NK cell activation is
mediated by receptors such as NK Group 2 member D (NKG2D), which regulates
NK cell function and cytotoxicity through the upregulation of cytokine production.
Individually, these treatments target only a limited subset of cancer patients and
often face great resistance rates after treatment. However, combining ICBs with NK
cell activation may produce a synergistic therapeutic effect, potentially improving
treatment outcomes. This perspective article discusses the mechanisms of action of
T cell-related PD-1/PDL1 pathways and NK cell activation through NKG2D, examining
current studies that provide a rationale for combined NK/T cell combination therapy.
*Corresponding author:
Yanzhang Wei The potential of this dual-combination approach to enhance anti-tumor immunity
(Ywei@clemson.edu) is highlighted. Future perspectives suggest the potential development of chimeric
Citation: Li J, Wei Y. Combination antibodies targeting both T cells and NK cells as a novel therapeutic strategy for
cancer therapy integrating T-cell cancer treatment.
immune checkpoint blockers and
natural killer cell activation. Gene
Protein Dis. 2024;3(4):3804. Keywords: Immune checkpoint blockers; PD-1/PD-L1; Natural killer cell activation; NKG2D
doi: 10.36922/gpd.3804
Received: May 31, 2024
Accepted: August 29, 2024
Published Online: October 4, 2024 1. Introduction
Copyright: © 2024 Author(s).
This is an Open-Access article Over the past several decades, immunotherapy has made remarkable strides in the
1
distributed under the terms of the treatment of human cancers. For example, adoptive cell transfer, chimeric antigen receptor
Creative Commons Attribution cell modification (CAR-T or CAR-NK), and immune checkpoint inhibitors (ICBs) have
License, permitting distribution,
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and reproduction in any medium, shown great clinical success. Among these immunotherapeutic approaches, ICBs, such
provided the original work is as monoclonal antibodies (mAb) targeting programmed death 1 (PD-1) and its ligand
properly cited. (PD-L1), or blocking antibodies that inhibit natural killer (NK) cell protein group 2-A
Publisher’s Note: AccScience (NKG2A) from interacting with tumor-expressed HLA-E, have shown promising
Publishing remains neutral with potential in treating various cancer types by targeting distinct inhibitory checkpoints
regard to jurisdictional claims in 4-8
published maps and institutional within different tumor microenvironments (TMEs). Since the initial discovery of
affiliations. “classical” ICB – PD-L1/PD1 – on T cells, which act as an inhibitory receptor allowing

Volume 3 Issue 4 (2024) 1 doi: 10.36922/gpd.3804