Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood

Brownlie, Demi; Scharenberg, Marlena; Mold, Jeff E.; Hård, Joanna; Kekäläinen, Eliisa; Buggert, Marcus; Nguyen, Son; Wilson, Jennifer N.; Al‐Ameri, Mamdoh; Ljunggren, Hans‐Gustaf; Marquardt, Nicole; Michaëlsson, Jakob

doi:10.1073/pnas.2016580118

Cited by 60 publications

(79 citation statements)

References 56 publications

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“…In recent years, it has been reported that NK cells can be converted to ILC1-like cells, which display poorer cytotoxic capabilities ( 60 ), as evident from reduced control over tumour burden and metastasis ( 61 , 62 ). Distinct from NK cells, the ILC1s do not express Eomes ( 60 ), further implicating this T-box transcription factor in marking functional and mature NK cells rather than its less cytotoxic ILC1 counterpart.…”

Section: Role Of T-box Transcription Factors In Cell Phenotype and Function: Parallels In Nk And T Cellsmentioning

confidence: 99%

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

2021

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Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.

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Section: Role Of T-box Transcription Factors In Cell Phenotype and Function: Parallels In Nk And T Cellsmentioning

confidence: 99%

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

2021

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“…Recent studies have revealed that NK cells are highly heterogeneous with different immune functions [25][26][27] .…”

Section: Il-12 Immunotherapy Prompts Nk Cells To Orchestrate An Anti-tumor Microenvironmentmentioning

confidence: 99%

Adaptive anti-tumor immunity is orchestrated by a population of CCL5-producing tissue-resident NK cells

Kirchhammer

Trefny

Natoli

et al. 2021

Preprint

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Targeting T cells for cancer immunotherapy commonly fails to generate lasting tumor control. Harnessing additional orchestrators of the immune response against tumors may enhance and broaden clinical benefit. Here, we demonstrate that therapeutic targeting of the IFNγ-IL-12 pathway relies on the amplification of anti-tumoral DC-T cell crosstalk by NK cells. Utilizing an engineered adenoviral platform for paracrine delivery into the tumor microenvironment, we show that IL-12 enhances functional DC-CD8 T cell interactions to generate profound anti-tumor immunity. This effect depends on the abundance of intra-tumoral NK cells and specifically their capacity to produce the DC chemoattractant CCL5. Failure to respond to IL-12 and other IFNγ-inducing therapies such as immune checkpoint blockade can be overcome by intra-tumoral therapeutic delivery of CCL5 resulting in the recruitment of cDC1s. Our findings reveal novel mechanistic insights how to enhance T cell-NK cell-DC crosstalks, enforcing a tumor-eliminating positive feedback mechanism to promote anti-tumor immunity and overcome resistance.

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“…Liver tissue is enriched with innate immune cells that can effectively and quickly defend against invading microorganisms and tumor transformation (3)(4)(5). Lymphocytes are classically viewed as continuously circulating in peripheral organs; however, recent studies demonstrate the existence of tissue-resident lymphocytes in the skin, lung, and intestinal mucosa and other peripheral organs, where they exert protective immunity to infection and malignancy (6)(7)(8)(9). Notably, the liver contains multiple resident lymphocytes including memory CD8 + T (T RM ) cells, invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and natural killer (NK) cells (10,11).…”

Section: Introductionmentioning

confidence: 99%

Murine CXCR3+CXCR6+γδT Cells Reside in the Liver and Provide Protection Against HBV Infection

Wang

Guan

et al. 2022

Front. Immunol.

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Gamma delta (γδ) T cells play a key role in the innate immune response and serve as the first line of defense against infection and tumors. These cells are defined as tissue-resident lymphocytes in skin, lung, and intestinal mucosa. They are also relatively abundant in the liver; however, little is known about the residency of hepatic γδT cells. By comparing the phenotype of murine γδT cells in liver, spleen, thymus, and small intestine, a CXCR3+CXCR6+ γδT-cell subset with tissue-resident characteristics was found in liver tissue from embryos through adults. Liver sinusoidal endothelial cells mediated retention of CXCR3+CXCR6+ γδT cells through the interactions between CXCR3 and CXCR6 and their chemokines. During acute HBV infection, CXCR3+CXCR6+ γδT cells produced high levels of IFN-γ and adoptive transfer of CXCR3+CXCR6+ γδT cells into acute HBV-infected TCRδ−/− mice leading to lower HBsAg and HBeAg expression. It is suggested that liver resident CXCR3+CXCR6+ γδT cells play a protective role during acute HBV infection. Strategies aimed at expanding and activating liver resident CXCR3+CXCR6+ γδT cells both in vivo or in vitro have great prospects for use in immunotherapy that specifically targets acute HBV infection.

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Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood

Cited by 60 publications

References 56 publications

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

Adaptive anti-tumor immunity is orchestrated by a population of CCL5-producing tissue-resident NK cells

Murine CXCR3+CXCR6+γδT Cells Reside in the Liver and Provide Protection Against HBV Infection

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