Ly49 Family Receptors Are Required for Cancer Immunosurveillance Mediated by Natural Killer Cells

Tu, Megan M.; Mahmoud, Ahmad Bakur; Wight, Andrew; Mottashed, Amelia; Bélanger, Simon; Rahim, Mir Munir A.; Abou-Samra, Elias; Makrigiannis, Andrew P.

doi:10.1158/0008-5472.can-13-3021

Cited by 31 publications

(32 citation statements)

References 41 publications

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“…47 Killer cell lectin-like receptor, subfamily A, member 3 (Klra3) is an NK-cell receptor that is required for activation. Major histocompatibility complex class I recognition receptor (Ly49I, Klra9) serves as an NK-cell activator 48 and is involved in controlling cytomegalovirus infection. 49 The reduction in receptors for NK-cell activation would explain the higher degree of lung carcinoma development in RAG1 −/− Sgo1 −/+ animals, because of reduced NK-cell-mediated surveillance for mutagenic CIN cells.…”

Section: Resultsmentioning

confidence: 99%

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

et al. 2016

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Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment. Previously Shugoshin-1 (Sgo1−/+) mice, a transgenic mouse model of CIN, showed mild proneness to spontaneous lung and liver cancers. In this study, adoptive (T/B-cell based) immunity-deficient RAG1−/− Sgo1−/+ double mutant mice developed lung adenocarcinomas more aggressively than did Sgo1−/+ or RAG1−/− mice, suggesting immune system involvement in CIN-mediated lung carcinogenesis. To identify molecular causes of the lung adenocarcinoma, we used systems biology approach, comparative RNAseq, to RAG1−/− and RAG1−/− Sgo1−/+. The comparative RNAseq data and follow-up analyses in the lungs of naive Sgo1−/+ mice demonstrate that, (i) glutathione is depleted, making the tissue vulnerable to oxidative stress, (ii) spontaneous DNA damage is increased, (iii) oncogenic Wnt signaling is activated, (iv) both major branches of the immune system are weakened through misregulations in signal mediators such as CD80 and calreticulin and (v) the actin cytoskeleton is misregulated. Overall, the results show multi-faceted roles of CIN in lung carcinoma development in Sgo1−/+ mice. Our model presents various effects of CIN and will help to identify potential targets to prevent CIN-driven carcinogenesis in the lung.

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Section: Resultsmentioning

confidence: 99%

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

et al. 2016

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“…The importance of Ly49 in NK cell-mediated tumor immunosurveillance and MHC I-directed tumor editing was recently demonstrated in a study using Ly49-deficient mice (101). Another study demonstrated that human tumors reduced activating NK cell receptor (NKp30) recognition by NK cells by shedding B7-H6 from their cell surface (102).…”

Section: Other Parameters Impacting Cd8 + T Cells In Cancer Immunoedimentioning

confidence: 99%

From mice to humans: developments in cancer immunoediting

Teng¹,

Galon²,

Fridman³

et al. 2015

Journal of Clinical Investigation

287

219

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“…37 The Ly49 family of receptors is known to help in NK cell education, licensing to control cancer growth and immunosurveillance. 38 Furthermore, Ly49H C NK cells have been implicated to differentiate into long-lived memory NK cells during MCMV infection and provide better protection to the host. 39 Our data showing significantly reduced Ly49D and Ly49H expression in tumor infiltrating CD27 C…”

Section: Cd11bmentioning

confidence: 99%

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

et al. 2016

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Natural killer (NK) cells are known to have effector and cytolytic properties to kill virus infected or tumor cells spontaneously. Due to these properties, NK cells have been used as an adoptive cellular therapy to control tumor growth in various clinical trials but have shown limited clinical benefits. This indicates that our knowledge about phenotypic and functional differences in NK cells within the tumor microenvironment and secondary lymphoid tissues is incomplete. In this work, we report that B16F10 cellinduced melanoma recruits the CD11b C CD27C subset of NK cells at a very early stage during tumor progression. These intratumoral NK cells showed increased expression of CD69, reduced inhibitory receptor KLRG1, and decreased proliferative ability. As compared to splenic NK cells, intratumoral NK cells showed decreased expression of activating receptors NKG2D, Ly49D and Ly49H; increased inhibitory receptors, NKG2A and Ly49A; decreased cytokines IFNg and GM-CSF; decreased cytokine receptors IL-21R, IL-6Ra, and CD122 expression. Depletion of NK cells led to decrease peripheral as well as intratumoral effector CD4 C T-bet C cells (Th1), and increased tumor growth. Furthermore, purified NK cells showed increased differentiation of Th1 cells in an IFNg-dependent manner. Anti-NKG2D in the culture promoted differentiation of effector Th1 cells. Collectively, these observations suggest that intratumoral NK cells possess several inhibitory functions that can be partly reversed by signaling through the NKG2D receptor or by cytokine stimulation, which then leads to increased differentiation of effector Th1 cells.

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Ly49 Family Receptors Are Required for Cancer Immunosurveillance Mediated by Natural Killer Cells

Cited by 31 publications

References 41 publications

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

From mice to humans: developments in cancer immunoediting

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

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