Recent work by Böttcher and colleagues defines a new role for Natural Killer cells in the anti-tumor immune response, arriving early into the tumor microenvironment before passing the baton to DC1 dendritic cells. DC1 dendritic cells subsequently activate CD8+ T cells resulting in effective anti-tumor immunity. This work highlights the cooperative nature of anti-tumor immunity set in motion by Natural Killer cells, and immune evasion by tumors through their exclusion.National Cancer Institute (U.S.) (R00CA204595

Duong, Ellen

Fessenden, Timothy B

Spranger-Zimmermann, Stefani

Journal for ImmunoTherapy of Cancer

DSpace@MIT

COMMENTARY Open AccessA team effort: natural killer cells on the firstleg of the tumor immunity relay raceTimothy B. Fessenden1, Ellen Duong2 and Stefani Spranger1,2,3*AbstractRecent work by Böttcher and colleagues defines a new role for Natural Killer cells in the anti-tumor immune response,arriving early into the tumor microenvironment before passing the baton to DC1 dendritic cells. DC1 dendritic cellssubsequently activate CD8+ T cells resulting in effective anti-tumor immunity. This work highlights the cooperativenature of anti-tumor immunity set in motion by Natural Killer cells, and immune evasion by tumors through theirexclusion.Main textSustained infiltration of CD8+ T cells into the tumormicroenvironment has been shown to generate an im-mune suppressive microenvironment through the upregu-lation of immune inhibitory molecules, including PD-L1(programmed death receptor ligand 1) on tumor cells ormyeloid cells [1]. Accordingly, the majority of melanomapatients with a T-cell inflamed tumor microenvironmentresponds to checkpoint blockade therapy targetingimmune inhibitory pathways such as PD-1:PD-L1 interac-tions, while non-T cell-inflamed tumors tend to be refrac-tory to this therapy [2]. Unraveling the cellular andmolecular determinants of T cell recruitment to andretention in solid tumors is therefore a crucial step towardimproving existing immunotherapies.Antigen-presenting cells, in particular dendritic cells(DC), are known to orchestrate initial activation of T cellsin the tumor-draining lymph node [1]. In particular,cross-presenting CD103+ DC (also known as DC1 orClec9a + DC) appear to be critical for priming CD8+ Tcells [3]. Recent reports have defined a distinct role forCD103+ DC residing within the tumor microenviron-ment, where they cooperate with CD8+ cytotoxic T cellsto recognize and clear tumor cells. Consequently, tumorsable to exclude CD103+ DC can successfully evade T-cellmediated immune control [4, 5]. However, ourunderstanding of the recruitment and retention oftumor-resident DC populations is still sparse.Böttcher et al. addressed this question using a melan-oma tumor model previously reported to exclude T cellsand CD103+ DC through the upregulation of cyclooxy-genase enzymes COX-1 and COX-2 (encoded by ptgs1and ptgs2) and their catalytic product, prostaglandin E2(PGE2) [6]. In addition to the exclusion of CD103+ DC,they observed a stark reduction in the recruitment ofNatural Killer (NK) cells into tumors [7]. Assessing thechemokine expression profile of tumor-residing immunecell subsets, the authors showed that XCL1 is producedexclusively by NK cells while CCL5 is secreted by bothNK cells and CD8+ effector T cells. Both XCL1 andCCL5 as well as CCL4 have previously been reported toattract CD103+ DC to inflammatory sites through bindingto XCR1/CCR5 chemokine receptors [4, 8], results thatwere confirmed in this study. In contrast to observationsby Böttcher et al., however, previous studies found chemo-kine production originated from non-immune cells, sug-gesting that the source for chemokines might be highlycontext dependent.Depletion of NK cells resulted in failed recruitment ofCD103+ DC and immune evasion by tumors. In vitro ana-lysis showed that tumor-derived PGE2 resulted in dimin-ished secretion of CCL5 and XCL1 by NK cells andincreased NK cell death [7]. The observation of increasedlymphocyte death in tumors with high levels of PGE2agrees with previous reports. A study of ovarian cancerfound that COX-2/PGE2 signaling caused increasedexpression of Fas-ligand on endothelial cells, which inturn increased apoptosis of infiltrating T cells and resulted* Correspondence: spranger@mit.edu1Koch Institute for Integrative Cancer Research at MIT, 500 Main Street,Cambridge, MA 02139, USA2Massachusetts Institute of Technology, Department of Biology, Cambridge,USAFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Fessenden et al. Journal for ImmunoTherapy of Cancer  (2018) 6:67 https://doi.org/10.1186/s40425-018-0380-4in a non-T cell-inflamed tumor microenvironment [9].Both studies show a cell death-related phenotype, howeversince NK cell death was observed ex vivo, the molecularmechanism appear to be distinct and should be fullyelucidated.The authors then validated their findings using patientsamples and found that indeed NK cells are the domin-ant source of XCL1/2, while CD8+ effector T cells pro-duce high levels of CCL5. Using human RNA transcriptdata, the authors provide further evidence supportingthe concept that NK cells recruit CD103+ DC, which inturn are required for the recruitment of effector T cells.Previous work has shown that CD103+ DC are criticalfor the recruitment of effector T cells into the tumormicroenvironment through the secretion of CXCL9 andCXCL10 [5, 6]. Likewise, these studies provided evidencethat restoration of CD103+ DC infiltration mediatesregained responsiveness to immunotherapy.Considering these observations in conjunction withthose made by Böttcher and colleagues, it is plausible tosuggest that anti-tumor immunity may operate as a relayrace in which immune cells recruit each other to passthe tumor-reactive “baton” (See Fig. 1). Such cooperationensures the sequential recruitment of NK cells, CD103+DC, and most importantly CD8+ effector T cells into thetumor microenvironment. It is worth noting that, similarto effector T cells, NK cells can also be recruited byCXCL9 and CXCL10.Meanwhile, CD8+ effector T cells are also a sourceof CCL4, CCL5 and XCL1. This redundancy inchemokine-mediated immune cell recruitment sug-gests a strong positive feedback loop, and highlightsthe importance of the recruitment and activation ofearly effector cells such as NK cells.The canonical cytolytic role of NK cells can directly orindirectly contribute to tumor control.However, Böttcher et al. make several intriguing observa-tions regarding the role of NK cells during an anti-tumorimmune response that go beyond their classically describedfunction. The intriguing notion that innate lymphocytescan be recruited into the tumor at very early stages couldexplain the recruitment of CD103+ DC into tumors lackingchemokine production. In conjunction with the observationthat PGE2 inhibits NK cell function, it could therefore bespeculated that PGE2 mediates inhibition of anti-tumor im-mune responses at early stages of tumor development. In-deed, expression of cyclooxygenases and production ofPGE2 has been linked to malignant transformation in mul-tiple tissues and therefore is an early event in tumor devel-opment [10]. However, additional studies will beneeded to elucidate how NK cells are activated andrecruited into early tumor lesions. Similarly, whetherNK cell activation is required in all cancer types todrive recruitment and retention of CD103+ DC andCD8+ effector T cells merits further investigation.Determining the mechanism of NK cell recruitmentcould potentially lead to direct targeting of NK cellrecruitment as a therapeutic target to start thetumor-immune “relay race.” This therapeutic approachcould convert immunotherapy-resistant, non-Tcell-inflamed tumors into checkpoint blockadetherapy-sensitive T cell-inflamed microenvironments,potentially independent of the tumor type andmolecular mechanism for exclusion of CD103+ DCand CD8+ T cells.FundingThis work was funded by NCI R00CA204595 to SS.Authors’ contributionsTF, ED, and SS wrote and edited the manuscript. All authors read andapproved the final manuscript.Ethics approval and consent to participateNot ApplicableConsent for publicationNot applicableFig. 1 The tumor-immune relay race. Natural Killer (NK) cells are thefirst to arrive in the tumor microenvironment and recruit CD103+dendritic cells (DC) through the secretion of chemokines. ActivatedDC then transport antigen from the tumor to the tumor-draininglymph node where they prime T cells (T). DC residence in tumors isalso critical to drive effector T cell recruitment into the tumormicroenvironment. Sensing and eradication of tumors is thus theresult of collaboration of distinct cell types within thetumor microenvironmentFessenden et al. Journal for ImmunoTherapy of Cancer  (2018) 6:67 Page 2 of 3Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Koch Institute for Integrative Cancer Research at MIT, 500 Main Street,Cambridge, MA 02139, USA. 2Massachusetts Institute of Technology,Department of Biology, Cambridge, USA. 3Howard S. and Linda B. SternCareer Development Professor, 77 Massachusetts Avenue, Cambridge, MA02139, USA.Received: 26 April 2018 Accepted: 20 June 2018References1. Spranger S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. IntImmunol. 2016;28:383–91.2. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, et al.PD-1 blockade induces responses by inhibiting adaptive immune resistance.Nature. 2014;515:568–71.3. Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z,et al. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. CancerCell. 2012;21:402–17.4. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signallingprevents anti-tumour immunity. Nature. 2015;523:231–5.5. Spranger S, Dai D, Horton B, Gajewski TF. Tumor-residing Batf3 dendriticcells are required for effector T cell trafficking and adoptive T cell therapy.Cancer Cell. 2017;31:711–723.e4.6. Zelenay S, van der Veen AG, Böttcher JP, Snelgrove KJ, Rogers N, Acton SE,et al. Cyclooxygenase-dependent tumor growth through evasion ofimmunity. Cell. 2015;162:1257–70.7. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M,Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into thetumor microenvironment promoting Cancer immune control. Cell. 2018;172:1022–1037.e14.8. Alexandre YO, Ghilas S, Sanchez C, Le Bon A, Crozat K, Dalod M. XCR1dendritic cells promote memory CD8 T cell recall upon secondary infectionswith listeria monocytogenes or certain viruses. J Exp Med. 2016;213:75–92.9. Motz GT, Santoro SP, Wang L-P, Garrabrant T, Lastra RR, Hagemann IS, et al.Tumor endothelium FasL establishes a selective immune barrier promotingtolerance in tumors. Nat Med. 2014;20:607–15.10. Wang D, DuBois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10:181–93.Fessenden et al. Journal for ImmunoTherapy of Cancer  (2018) 6:67 Page 3 of 3

A team effort: natural killer cells on the first leg of the tumor immunity relay race

Abstract Recent work by Böttcher and colleagues defines a new role for Natural Killer cells in the anti-tumor immune response, arriving early into the tumor microenvironment before passing the baton to DC1 dendritic cells. DC1 dendritic cells subsequently activate CD8+ T cells resulting in effective anti-tumor immunity. This work highlights the cooperative nature of anti-tumor immunity set in motion by Natural Killer cells, and immune evasion by tumors through their exclusion

A team effort: natural killer cells on the first leg of the tumor immunity relay race

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