Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence

Abstract

There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules associated with immune exhaustion (such as PD-1, but also TIGIT, and LAG-3) has led to a revolution in oncology with dramatic benefits in a growing list of solid and hematologic malignancies. Given this success in reinvigorating exhausted T cells and the related anti-tumor effects, there are increasing efforts to apply immune checkpoint blockade to other exhausted immune cells beyond T cells. One approach involves the reinvigoration of "exhausted" NK cells, a non-T, non-B lymphoid cell of the innate immune system. However, in contrast to the more well-defined and established molecular, genetic, and immunophenotypic characteristics of T cell exhaustion, a consensus on the defining functional and phenotypic features of NK "exhaustion" is less clear. As is well-known from T cell biology, separate and distinct molecular and cellular processes including senescence, anergy and exhaustion can lead to diminished immune effector function with different implications for immune regulation and recovery. For NK cells, it is unclear if exhaustion, anergy, and senescence entail separate and distinct entities of dysfunction, though all are typically characterized by decreased effector function or proliferation. In this review, we seek to define these distinct spheres of NK cell dysfunction, analyzing how they have been shown to impact NK biology and clinical applications, and ultimately highlight key characteristics in NK cell function, particularly in relation to the role of "exhaustion."

Unexpected central-memory CD8+ T cell reduction hampers the antitumor efficacy of mogamulizumab (anti-CC chemokine receptor 4 mAb) treatment

“…Due to the uncoupling of clinical e cacy and CCR4 expression in eTreg cells and central-memory CD8 + T cells, we further explored the potential involvement of NK cell function in the clinical e cacy of mogamulizumab because mogamulizumab possesses enhanced antibody-dependent cellular cytotoxicity (ADCC) activity via a defucosylated Fc region 28 . NK cells exhibited an exhausted phenotype, which was determined by the expression of PD-1 and LAG-3, in some patients particularly in long-term survivors ( Figure 4A and 4B), indicating the presence of impaired ADCC activity in long-term survivors 29 . Patients, from whom the data regarding both CCR4 expression and NK cell exhaustion were available, were divided into long-term survivors and short-term survivors, and CCR4 expression and NK cell exhaustion were compared.…”

Prostate cancer peripheral blood NK cells show enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 production, and secrete monocyte-recruiting and polarizing factors

“…NK cells have been found to be compromised in several cancers [3,6,[9][10][11][12][13]15,18,19,24,25,38]. NK cell contribution to tumour progression goes beyond the mechanism of tumour escape and immunosuppression [3,[10][11][12]24,25] .…”

“…As for several immune cells [3][4][5][6]8], NK cells have been described to acquire a tolerogenic behaviour and to be altered in their cytotoxic activities [3][4][5][6][10][11][12][13][14][15][16], they represent still an under investigated cell population and only few studies demonstrated pro-inflammatory angiogenic cancer cell growth promoting activities in cancers [3,[10][11][12]14]. Major mechanisms associated with impaired NK cell function in cancer patients, are downregulation of lytic perforin/granzyme production accompanied with reduction of degranulation capabilities, together with reduction of NKG2D (the major NK cell activation receptor) expression [17][18][19]. In prostate cancer, the ligands for NKp30 and NKp46 are expressed on NK cells from patients with primary tumours but not on benign prostate hyperplasia [20].…”

Overcoming the UCB HSCs –Derived NK Cells Dysfunctionality through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

“…Although many efforts have been expended to date to apply NK cells derived from peripheral blood to adoptive therapy of solid and hematopoietic cancers (Klingemann, 2015;Lim et al, 2015); this approach has encountered several pitfalls such as insu cient cell number, limited source accessibility, lower response to stimulants, decreased expansion potential and increased dysfunctionality. To address these limitations, other Moreover, surface receptors inducing inhibitory signals in NK cells, such as NKG2A are overexpressed in malignancies and chronic infections (Chester, Fritsch, & Kohrt, 2015;Judge et al, 2020). NKG2A is one of the most important inhibitory receptors which plays a role in the dysfunctionality of NK cells in the patients with the mentioned diseases through inducing IL-10 production.…”

“…NKG2A is one of the most important inhibitory receptors which plays a role in the dysfunctionality of NK cells in the patients with the mentioned diseases through inducing IL-10 production. Other inhibitory receptors having a prominent role in NK cells inactivation are Tim3 and PD-1 (Chan, Smyth, & Martinet, 2014;Judge et al, 2020;Vivier, Nunes, & Vely, 2004;Watzl & Long, 2010).…”