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Patrolling Monocytes Control NK Cell Expression of Activating and Stimulatory Receptors to Curtail Lung Metastases

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Patrolling Monocytes Control NK Cell Expression of Activating and Stimulatory Receptors to Curtail Lung Metastases Patrolling Monocytes Control NK Cell Expression of Activating and Stimulatory Receptors to Curtail Lung Metastases This information is current as Prakash Babu Narasimhan, Tobias Eggert, Yanfang Peipei of September 27, 2021. Zhu, Paola Marcovecchio, Melissa A. Meyer, Runpei Wu and Catherine C. Hedrick J Immunol published online 25 November 2019 http://www.jimmunol.org/content/early/2019/11/22/jimmun ol.1900998 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/11/22/jimmunol.190099 Material 8.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 25, 2019, doi:10.4049/jimmunol.1900998 The Journal of Immunology Patrolling Monocytes Control NK Cell Expression of Activating and Stimulatory Receptors to Curtail Lung Metastases Prakash Babu Narasimhan, Tobias Eggert, Yanfang Peipei Zhu, Paola Marcovecchio, Melissa A. Meyer, Runpei Wu, and Catherine C. Hedrick The role of nonclassical, patrolling monocytes in lung tumor metastasis and their functional relationships with other immune cells remain poorly defined. Contributing to these gaps in knowledge is a lack of cellular specificity in commonly used approaches for depleting nonclassical monocytes. To circumvent these limitations and study the role of patrolling monocytes in melanoma metas- tasis to lungs, we generated C57BL/6J mice in which the Nr4a1 superenhancer E2 subdomain is ablated (E22/2 mice). E22/2 mice lack nonclassical patrolling monocytes but preserve classical monocyte and macrophage numbers and functions. Interestingly, NK Downloaded from cell recruitment and activation were impaired, and metastatic burden was increased in E22/2mice. E22/2 mice displayed un- changed “educated” (CD11b+CD27+) and “terminally differentiated” (CD11b+CD272) NK cell frequencies. These perturbations were accompanied by reduced expression of stimulatory receptor Ly49D on educated NK cells and increased expression of inhibitory receptor NKG2A/CD94 on terminally differentiated NK cells. Thus, our work demonstrates that patrolling monocytes play a critical role in preventing lung tumor metastasis via NK cell recruitment and activation. The Journal of Immunology, 2020, 204: 000–000. http://www.jimmunol.org/ ver the past decade, numerous studies have implicated bone marrow chimeric mice. Ab-mediated depletion of NK cells monocytes in the regulation of NK cell activity (1–5). In reversed the protective effect of monocytes against lung metastasis, O cancer, monocytes both enhance (1, 2, 5) and inhibit (3, 4) highlighting the interplay between these two immune cell types. NK cell antitumor immunity. Classical, inflammatory monocytes Collaboration between patrolling monocytes and NK cells (CD14+CD162 in humans and Ly6C+CCR2+CX3CR1low in mice) against melanoma metastases has been further evidenced by have been linked to NK cell proliferation, cytotoxicity, and two recent studies (8, 9). First, Plebanek and colleagues show cytokine production. For example, TLR 4 activation upregu- that exosomes from poorly metastatic melanomas expand the lates expression of the NKG2D ligand MICA on CD14+ monocytes patrolling monocyte population in the bone marrow through and induces NK cell–dependent IFN-g production (5). These MICA- expression of Nr4a1. In agreement with our own findings, this by guest on September 27, 2021 expressing monocytes enhance NK cell, Ab-dependent cytotoxicity paper also found that depletion of NK cells partially reverses against Ab-labeled cancer cells (6). Few studies, in contrast, have the antimetastatic effect of patrolling monocytes (8). Second, explored the role of nonclassical, patrolling monocytes Kubo and colleagues (9) provide data indicating that the (CD16+CD14low/2 in humans and Ly6Clow/2CX3CR1high in presence of primary, s.c. melanomas inhibit formation of mice) on NK cell antitumor function. melanoma lung metastases by expanding patrolling monocyte- Our laboratory has demonstrated that patrolling monocytes re- mediated NK cells in the lung. duce metastatic burden in mouse models of both melanoma lung A major limitation of the aforementioned studies is that the metastasis and primary breast cancer with spontaneous metastasis experimental approaches used for depleting patrolling monocytes to the lung. We have also shown that this effect is partially de- are not cell specific and therefore reduce numbers of additional pendent on NK cells (7). Specifically, we found that, by producing cell types. Furthermore, genetic ablation of Nr4a1 in mice also chemokines CCL3, CCL4, and CCL5, patrolling monocytes affects macrophage function (10). We have overcome these ob- recruit NK cells to the lung. This involvement of monocytes in stacles by ablating an Nr4a1 superenhancer E2 subdomain in the prevention of lung tumor metastasis was confirmed in pa- mice, resulting in efficacious depletion of patrolling monocytes trolling monocyte-deficient, Nr4a1 whole-body knockout and while leaving classical monocyte and macrophage function un- affected (11). In this study, we describe the use of these animals (henceforth referred to as E22/2 mice) to confirm the role of Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA patrolling monocytes in NK cell–dependent prevention of mela- 92037 noma metastasis to lungs. In E22/2 mice, both recruitment and ORCIDs: 0000-0001-7111-7124 (P.B.N.); 0000-0001-6908-0860 (Y.P.Z.); 0000- 0003-3050-4819 (M.A.M.). activation of lung NK cells following i.v. injection of melanoma Received for publication August 19, 2019. Accepted for publication October 15, cells, as measured by a diverse set of surface receptors, were 2019. impaired in the absence of patrolling monocytes. In contrast, 2/2 This work was supported by the National Institutes of Health (NCI R01 CA202987 maturation of NK cells in E2 mice was unaffected. Long- and NCI U01 CA224766, both to C.C.H.). term monitoring of these mice showed increased metastatic Address correspondence and reprint requests to Dr. Catherine C. Hedrick, La Jolla burden in lungs, as assessed by imaging of melanoma luciferase Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: expression and tumor nodule count. In summary, our work in [email protected] this study shows that patrolling monocytes provide important The online version of this article contains supplemental material. signals for proper NK cell recruitment, activation, and thereby Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 antimetastatic function. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900998 2 PATROLLING MONOCYTES CONTROL METASTASIS VIA NK CELLS Materials and Methods tumors (7). In this study, we set out to more rigorously define Cells patrolling monocyte-mediated recruitment and activation of NK cells by analyzing the accumulation of these cells in lungs soon B16F10 melanoma and Yac-1 cells were obtained from American Type Culture Collection. B16F10-luciferase expressing cells (B16luc) were after metastatic seeding. To this end, we studied the frequency + + low/2 kindly provided by the Kronenberg laboratory (La Jolla Institute for Im- of total monocytes (CD11b CD115 ), Ly6C monocytes 2 2 munology). Cell lines were tested for being pathogen free and maintained (CD11b+CD115+Ly6Clow/ ), and NK cells (CD3 NK1.1+)byflow in DMEM containing 10% heat-inactivated FBS, 2 mmol/l l-glutamine, cytometry(allAbslistedinTableI)at4and8hafteri.v.in- 1 mmol/l sodium pyruvate, 50 U/ml penicillin, and 50 mg/ml streptomycin. jection of B16F10 melanoma cells in wild-type (C57BL/6J) mice. Mice A significant increase in NK cell frequency (from 9 to 15%) was observed at 8 h after B16F10 melanoma cell seeding and C57BL/6J mice were purchased from The Jackson Laboratory. Congenic low/2 E22/2 mice were previously described (11) and maintained in house. In all coincided with a significant 2-fold expansion of Ly6C experiments, age-matched 8- to 12-wk-old male mice were used. Three monocytes (Fig. 1A, 1B). To confirm activation of recruited hundred thousand B16F10 or B16luc melanoma cells were injected via tail NK cells after B16F10 injection, we analyzed NK cells for the vein into recipient mice. After indicated time points, mice were euthanized expression of activating surface receptors CD226 and NKG2D. by CO2 inhalation, and lungs were perfused with 10 ml of PBS and har- vested for subsequent analyses. For metastatic burden quantification, lu- We observed that the fraction of activated NK cells signifi- ciferase activity was measured 13 d after i.v. injection of melanoma cells cantly increased upon recruitment to metastatic lungs, with using an Ami HT Bioluminescence Imager (Spectral Instruments Imaging) the NKG2D+NK
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