NK cells in the tumor microenvironment: Prognostic and theranostic impact. Recent advances and trends

Russick, Jules; Torset, Carine; Hemery, Edouard; Cremer, Isabelle

doi:10.1016/j.smim.2020.101407

Cited by 44 publications

(23 citation statements)

References 143 publications

(153 reference statements)

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“…The NK cell-cDC1 axis is integral for controlling immune responses to cancer and is linked to increased patient survival and/or responses to immunotherapies in metastatic melanoma, head and neck squamous cell carcinoma, triple negative breast cancer, and neuroblastoma ( 16 , 17 , 26 ). It is important to note that in certain tumor settings NK cells have been shown to have inhibitory effects on DC functions ( 50 – 52 ) and DCs can have inhibitory effects on NK cell functions [rev. in ( 44 – 47 )].…”

Section: The Natural Killer–dendritic Cell Innate Immune Axis In Cancmentioning

confidence: 99%

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

Peterson

Barry

2021

Front. Immunol.

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Natural killer (NK) cells and dendritic cells (DCs) are crucial mediators of productive immune responses to infection and disease. NK cells and a subtype of DCs, the type 1 conventional DCs (cDC1s), are individually important for regulating immune responses to cancer in mice and humans. Recent work has found that NK cells and cDC1s engage in intercellular cross-talk integral to initiating and coordinating adaptive immunity to cancer. This NK cell–cDC1 axis has been linked to increased overall survival and responses to anti-PD-1 immunotherapy in metastatic melanoma patients. Here, we review recent findings on the role of NK cells and cDC1s in protective immune responses to cancer and immunotherapy, as well as current therapies targeting this NK cell–cDC1 axis. Further, we explore the concept that intercellular cross-talk between NK cells and cDC1s may be key for many of the positive prognostic associations seen with NK cells and DCs individually. It is clear that increasing our understanding of the NK cell–cDC1 innate immune cell axis will be critical for the generation of novel therapies that can modulate anti-cancer immunity and increase patient responses to common immunotherapies.

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Section: The Natural Killer–dendritic Cell Innate Immune Axis In Cancmentioning

confidence: 99%

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

Peterson

Barry

2021

Front. Immunol.

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“…7 Such functions do not emerge from the recognition of a specific antigen, as in the case of CD8 + cytotoxic T lymphocytes (CTLs), 8,9 but are tightly regulated by the balance between inhibitory and stimulatory signals that are conveyed to NK cells by a large panel of membrane receptors upon interaction with potential target cells. 10,11 In line with the robust cytotoxic potential of NK cells, their abundance as well as the relative levels of inhibitory and stimulatory NK cell receptors have been attributed prognostic or predictive value in a variety of oncological settings, 1,12 including acute myeloid leukemia (AML). 13,14 AML is a particularly challenging malignancy for which hematopoietic stem cell transplantation (HSCT) represents the primary therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

“…In line with the robust cytotoxic potential of NK cells, their abundance as well as the relative levels of inhibitory and stimulatory NK cell receptors have been attributed prognostic or predictive value in a variety of oncological settings, 1 , 12 including acute myeloid leukemia (AML). 13 , 14 AML is a particularly challenging malignancy for which hematopoietic stem cell transplantation (HSCT) represents the primary therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

et al. 2021

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Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8 + cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyteassociated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.

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“…Besides, the adoptive NK cell therapy on immunodeficient mice proved UQCRC1 overexpression in PC resulted in a poor response to NK cell immunotherapy. In the TME, tumor cells have developed diverse skills to escape NK cell attack ( 43 ), such as altering the chemokine ligands production, shedding ligands for activating NK cell receptors, and secreting immunosuppressive molecules. Mitochondrial dysfunction has also been reported to mediate inhibition of intra-tumoral NK cell functions.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Mitochondrial UQCRC1 in Pancreatic Cancer Impairs Antitumor Immunity of Natural Killer Cells via Elevating Extracellular ATP

et al. 2022

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Pancreatic cancer (PC) is one of the most lethal malignancies characterized by a highly immunosuppressive tumor microenvironment (TME). Previously, we have reported that ubiquinol-cytochrome c reductase core protein I (UQCRC1), a key component of mitochondrial complex III, is generally upregulated in PC and produces extracellular ATP (eATP) to promote PC progression. Here, we sought to investigate whether the oncogenic property of UQCRC1 is generated through its effects on natural killer (NK) cells in the TME. We found that UQCRC1 overexpression in PC cells inhibited cytotoxicity of NK cells, as well as the infiltration of NK cells toward PC, whereas knockdown of UQCRC1 enhanced the cytotoxicity and chemotaxis of NK cells. Adoptive NK cell therapy in the subcutaneous mouse model and CIBERSORTx analysis with human PC specimens confirmed UQCRC1 elicited immunosuppressive effects on NK cells. Such UQCRC1-induced impairment of NK cells was mediated by eATP and its metabolite adenosine via P2Y11R and A2AR, respectively. Mechanistically, we found the UQCRC1/eATP axis reduced the expression of chemokine CCL5 in cancer cells and altered the balance of activating receptor DNAM-1 and inhibitory receptor CD96 on NK-92MI cells, resulting in decreased chemotaxis and exhausted phenotype of NK-92MI cells. Taken together, our study provides the evidence to support a novel mechanism by which energy metabolism change in cancer cells remodels the TME and impedes NK cell surveillance. It also suggests that targeting UQCRC1 may be a potential combined strategy for PC immunotherapy.

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NK cells in the tumor microenvironment: Prognostic and theranostic impact. Recent advances and trends

Cited by 44 publications

References 143 publications

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

Increased Expression of Mitochondrial UQCRC1 in Pancreatic Cancer Impairs Antitumor Immunity of Natural Killer Cells via Elevating Extracellular ATP

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