Harnessing NK Cell Checkpoint-Modulating Immunotherapies

Abstract

<jats:p>During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.</jats:p>

A Detailed View of KIR Haplotype Structures and Gene Families as Provided by a New Motif-Based Multiple Sequence Alignment

“…Within a given NK cell, KIR expression is stochastic, depending on the epigenetic profiles, inter-and intra-genic content of the haplotypes, binding alleles or lack thereof, methylation status, alternative splicing, and randomness (4)(5)(6). Besides investigating KIR in the context of viruses and pregnancy, medicine is also studying its effects in cancer, hematopoietic stem cells transplants, various autoimmune diseases, and immunotherapy (7)(8)(9).…”

Heme oxygenase 1 overexpression induces immune evasion of acute myeloid leukemia against natural killer cells by inhibiting CD48

“…The present study further deepened our current understanding of the immunological roles of HO1 by demonstrating NK dysfunction caused by HO1. Innate immunity mediated by NK cells is reportedly critical for attacking tumors, especially when acquired immunity is exhausted and dysfunctional [ 37 , 38 ], and tumor cells express no or rare MHC necessary for the induction and activation of T cells [ 39 ]. Therefore, anti-HO1 therapy that restores NK immunity may be widely useful for treating cancer, especially in AML patients with high HO1 and Sirt1 expression.…”

Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors

“…Further, TIM-3 expression levels are correlated with the stage of the disease. Several anti-TIM-3 Abs are to be tested in Phase I or II clinical trials: TSR-022 by Tesaro, LY3321367 by Eli Lilly, MGB453 by Novartis, Sym023 by Symphogen, and BGB-A425 by Beigene ( 65 , 66 ). The antibodies are often applied in combination with anti-PD-1 or anti-LAG-3 Abs in advanced solid tumors or AML.…”

“…As PVR expression is associated with unfavorable prognosis in many solid tumors, such as colon, breast, lung, and pancreatic cancers, the “PVR-TIGIT axis” has been suggested as a novel target in immune checkpoint therapy ( 77 ). Notably, tiragolumab, an anti-TIGIT Ab developed by Genentech, is already being evaluated in two independent Phase-III clinical trials for small cell lung cancer and non-small cell lung cancer with atezolizumab, an anti-PD-L1 Ab ( 66 ), and chemotherapy. There are two other anti-TIGIT Abs, MTIG7192A and AB154, in Phase I or II trials for various solid tumors.…”