Immunity

Previews In their study Perry et al. (2014) judiciously summoned up an assembly of highly informative and complementary methods, which allowed them to clear up some smoldering and contentious issues surrounding thymic tolerance induction. At the same time they made important and surprising observations. The generous sharing by mTECs of their most precious asset, the promiscuously expressed self-antigen pool, with their DC neighbors and its essential role in shaping the Treg cell repertoire, is perhaps the most intriguing and provocative discovery. Finding out the raison d’eˆtre and the cellular and molecular underpinning of this remarkable cellular

cooperation should prove both challenging and rewarding.

Klein, L., Kyewski, B., Allen, P.M., and Hogquist, K.A. (2014). Nat. Rev. Immunol. 14, 377–391. Liston, A., Lesage, S., Wilson, J., Peltonen, L., and Goodnow, C.C. (2003). Nat. Immunol. 4, 350–354.

REFERENCES Cowan, J.E., Parnell, S.M., Nakamura, K., Caamano, J.H., Lane, P.J.L., Jenkinson, E.J., Jenkinson, W.E., and Anderson, G. (2013). J. Exp. Med. 210, 675–681. Derbinski, J., Pinto, S., Ro¨sch, S., Hexel, K., and Kyewski, B. (2008). Proc. Natl. Acad. Sci. USA 105, 657–662. Hinterberger, M., Aichinger, M., Prazeres da Costa, O., Voehringer, D., Hoffmann, R., and Klein, L. (2010). Nat. Immunol. 11, 512–519. Humblet, C., Rudensky, A.Y., and Kyewski, B. (1994). Int. Immunol. 6, 1949–1958.

Malchow, S., Leventhal, D.S., Nishi, S., Fischer, B.I., Shen, L., Paner, G.P., Amit, A.S., Kang, C., Geddes, J.E., Allison, J.P., et al. (2013). Science 339, 1219–1224. Mathis, D., and Benoist, C. (2009). Annu. Rev. Immunol. 27, 287–312. Perry, J.S.A., Lio, C.-W.J., Kau, A.L., Nutsch, K., Yang, Z., Gordon, J.I., Murphy, K.M., and Hsieh, C.-S. (2014). Immunity 41, this issue, 414–426. Tykocinski, L.O., Sinemus, A., and Kyewski, B. (2008). Ann. N Y Acad. Sci. 1143, 105–122.

Targeting Foxp1 for Reinstating Anticancer Immunosurveillance Laurence Zitvogel1,2,3,4,* and Guido Kroemer1,5,6,7,8 1Gustave

Roussy Cancer Campus, Villejuif, France U1015, Villejuif, France 3Universite ´ Paris Sud-XI, Faculte´ de Me´decine, Le Kremlin Biceˆtre, France 4Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France 5Universite ´ Paris Descartes, Sorbonne Paris Cite´, Paris, France 6Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France 7Equipe 11 labellise ´ e Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France 8Po ˆ le de Biologie, Hoˆpital Europe´en Georges Pompidou, AP-HP, Paris, France *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2014.09.001 2INSERM

Transforming growth factor b (TGF-b) is a canonical immunosuppressive cytokine secreted by tumors. In this issue of Immunity, Stephen et al. (2014) reveal that tumor-derived TGF-b deactivates antitumor CD8+ T cell responses through T cell upregulation of the FoxP1 transcription factor. Transforming growth factor b (TGF-b) is well known for favoring tissue invasion and metastasis. Within tumors, it can be produced by multiple cell types including cancer cells themselves, dendritic cells (DCs), regulatory T (Treg) cells, and conventional T lymphocytes. TGF-b inhibits innate immunity through several mechanisms. Under the influence of TGF-b, neutrophils and macrophages convert from the N1 and M1 to the N2 and M2 phenotypes, respectively, becoming less cytotoxic and downregulating NF-kB activity. DCs exposed to TGF-b acquire a tolerogenic phenotype, contributing to Treg

cell expansion. TGF-b also downregulates NKp30 and NKG2D-dependent effector functions, thereby reducing the capacity of NK cells to secrete interferon-g (IFN-g) and to kill target cells. TGF-b also affects the adaptive arm of anticancer immunity, by influencing the survival, differentiation, proliferation, and apoptosis of most T cell subsets. Indeed, TGF-b promotes the differentiation of inducible Treg cells and the maintenance of natural Treg cells. TGF-b inhibits interferon-g (IFN-g) and T-bet expression by T helper 1 (Th1) cells and induces a shift toward a Th2 or Th17 differentiation state.

Finally, short-lived effector T cells residing in tumor beds are particularly susceptible to TGF-b-induced apoptosis (Flavell et al., 2010). In spite of this wealth of information, the precise molecular mechanisms accounting for the immunosuppressive effects of TGF-b signaling in growing tumors have remained elusive apart from the fact that, downstream of TGF-b receptor signaling, the transcription factor Smad3 participates in interleukin-2 (IL-2)-dependent and independent T cell repression (McKarns et al., 2004). In this issue of Immunity, Stephen et al. (2014) identified

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Immunity

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Foxp1 as a TGF-b-elicited Cd4-cre;Foxp1fl/fl mice) were T cell-intrinsic transcription able to proliferate within tufactor that is capable of mor beds, to secrete IFN-g switching off the AP1-depenand to synthesize Granzyme dent T cell activation proB, eventually leading to tumor gram. Activation of TGF-b regression. Therefore, rather receptors on tumor residing than reflecting a known type CD8+ T cells that are enof T cell dysfunction, Foxp1 gaging in the MHC class appears as a hallmark of I-dependent recognition of tu‘‘unresponsiveness’’ affecting mor cell antigens resulted in CD8+ T lymphocytes (Stephen et al., 2014). the upregulation of the nuThe function of Foxp1 has clear expression of Foxp1. previously been studied in Within the nuclei of CD8+ T cells, Foxp1 physically inmature CD8+ T cells through teracted with the newly transthe use of an inducible delelocated Smad2 and Smad3 tion model system. Loss of proteins, leading to the Foxp1 triggers IL-7-depenblockade of proliferation and dent T cell proliferation with major T cell functions inenhanced effector functions cluding the degranulation of (Feng et al., 2011). By negacytotoxic granules and cytotively regulating IL-7Ra kine release. Adoptively expression (more so in CD8+ than in CD4+ T cells) and transferred tumor-reactive signaling via the kinases Foxp1 / T cells (or T cells expressing an inhibitory mutant MEK and ERK, Foxp1 was Figure 1. Tumor-Associated Immunosuppressive TGF-b-Foxp1 Axis of the TGF-b receptor) were found to maintain the quiesTGF-b (in coordination with Cxcl12) is secreted from the tumor mass. These able to control the outgrowth cent status of mature naive + factors bind to their respective receptors on CD8 T cells. This results in of aggressive tumors without CD8+ T cells. Foxp1 and FoxP1 transcription factor association with Smad2 and Smad3 with subseFoxo1 have the ability to apparent toxicity. This effect quent translocation to the nucleus. The FoxP1-Smad2-Smad3 complex represses transcription of c-Jun and c-Myc. Consequently the T cell pool size bind to the same predicted could be phenocopied by the cannot expand and the tumor mass grows. FoxP1 also effects expression forkhead-binding site in the concomitant neutralization of of IFN-g and Granzyme B (Gzmb) in CD8+ T cells. Il7r enhancer region, which the chemokine Cxcl12 in suggests that these two trancombination with TGF-b, a manipulation that stimulated the anti- also highly expressed by T cells infiltrating scription factors might compete for the cancer activity of intratumoral T lympho- several cancer types including ovarian binding and antagonize each other to cytes (Figure 1). Transcriptional repres- and breast carcinomas. The upregulation regulate IL-7 receptor a (IL-7Ra) expression of c-Jun (and not NFAT), which is of Foxp1 transcription is observed in sion in T cells (Feng et al., 2011). Hence, one of the proteins composing the AP1 PD1 (more so than in PD1+) tumor-infil- it would be interesting to know whether complex, was necessary and sufficient trating lymphocytes, regardless of their T cell specific overexpression of Foxo1 to mediate Foxp1-induced T cell inhibition activation status, as judged from the might phenocopy the effects of Foxp1 in as much as enforced expression of c- expression of CD44, CD45RA, or CD69 deletion with respect to anticancer imJun could restore the T cell receptor (Doering et al., 2012; Stephen et al., mune responses. Is TGF-b the sole factor to upregulate (TCR)-driven proliferative capacity of 2014). To address the role of Foxp1 in CD8+ T cells in vitro (Stephen et al., 2014). controlling immunosurveillance, Stephen Foxp1 expression in the tumor microenviThe question then comes up as to et al. (2014) generated tumor-reactive ronment? Compared to quiescent periphwhether Foxp1 might be involved in CD8+ T cells by priming splenic naive eral T cells, intratumoral CD8+ T cells exT cell anergy (Schwartz, 2003), exhaus- T cells with syngeneic DCs pulsed with pressed higher amounts of the Foxp1a tion (Barber et al., 2006), or senescence irradiated ovarian tumor cells for 7 days isoform (or of the human ortholog (Akbar and Henson, 2011). This is a partic- (Stephen et al., 2014). In these ex vivo cul- FOXP1.1). In addition to TGF-b, ICAM1 ularly relevant query as uncontrolled ture assays, T cells failed to express rele- and Cxcl12 could reproducibly upreguoncogenic processes invariably offer an vant Foxp1 isoforms (Foxp1a and late Foxp1a in recently primed tumororchestrated microenvironment where Foxp1d). However, 48 hr after adoptive specific CD8+ T cells. In contrast, multiple anergy, exhaustion, and senescence ac- transfer into cancer-bearing mice, T cells other potentially immunosuppressive faccount for T cell dysfunctions and tumor that accumulated in tumor beds over- tors were unable to induce Foxp1a. This escape (Zitvogel et al., 2006, Pardoll, expressed Foxp1, indicating that origi- applies to myeloid suppressor cells, in2012). Foxp1 is not only overexpressed nally Foxp1 cells can acquire Foxp1 flammatory cytokines (such as IL-1b, in CD8+ T cells infiltrating mouse tumors. expression in the malignant microenviron- IL-6, IL-17, IL-23, CCL3, PGE2, VEGFa), Rather, its human ortholog, FOXP1, is ment. Only Foxp1-deficient T cells (from interleukins involved in T cell homeostasis 346 Immunity 41, September 18, 2014 ª2014 Elsevier Inc.

Immunity

Previews (such as IL-2, IL-7, IL-15), Th2 cell-associated cytokines, hypoxia, and estradiol (Stephen et al., 2014). Altogether, these findings underscore the relative ‘‘specificity’’ of the TGF-b-Foxp1 pathway. The present work might have important clinical implications. Inhibition of TGF-b and its signaling pathway with antibodies or antisense oligonucleotides or antisense molecules targeting TGF-bRI or RII is one possible strategy for boosting anticancer immune responses. Adoptive transfer of cytotoxic T lymphocytes engineered to express a dominant-negative mutant of the TGF-b receptor is also in early development. As an alternative, the emerging, ever-more practical genomeediting technologies (such as transcription-like effector nucleases and clustered regularly interspaced short palindromic

repeats) might be used to engineer T cells without TGF-b receptor subunits or downstream effectors including FOXP1 (Figure 1). Finally, the facts that FOXP1 must cooperate with other transcription factors including SMAD2 and SMAD3 and simultaneously must antagonize FOXO1 might be taken advantage of to create small molecules that disrupt specific protein-protein or protein-DNA interactions with the scope of creating a new category of checkpoint blockers. REFERENCES Akbar, A.N., and Henson, S.M. (2011). Nat. Rev. Immunol. 11, 289–295. Barber, D.L., Wherry, E.J., Masopust, D., Zhu, B., Allison, J.P., Sharpe, A.H., Freeman, G.J., and Ahmed, R. (2006). Nature 439, 682–687.

Doering, T.A., Crawford, A., Angelosanto, J.M., Paley, M.A., Ziegler, C.G., and Wherry, E.J. (2012). Immunity 37, 1130–1144. Feng, X., Wang, H., Takata, H., Day, T.J., Willen, J., and Hu, H. (2011). Nat. Immunol. 12, 544–550. Flavell, R.A., Sanjabi, S., Wrzesinski, S.H., and Licona-Limo´n, P. (2010). Nat. Rev. Immunol. 10, 554–567. McKarns, S.C., Schwartz, R.H., and Kaminski, N.E.J. (2004). Immunol. 172, 4275–4284. Pardoll, D.M. (2012). Nat. Rev. Cancer 12, 252–264. Stephen, T.L., Rutkowski, M.R., Allegrezza, M.J., Perales-Puchalt, A., Tesone, A.J., Svoronos, N., Nguyen, J.M., Sarmin, F., Borowsky, M.E., Tchou, J., and Conejo-Garcia, J.R. (2014). Immunity 41, this issue, 427–439. Schwartz, R.H. (2003). Annu. Rev. Immunol. 21, 305–334. Zitvogel, L., Tesniere, A., and Kroemer, G. (2006). Nat. Rev. Immunol. 6, 715–727.

Plague’s Partners in Crime Kimberly M. Davis1,2 and Ralph R. Isberg1,2,* 1Howard

Hughes Medical Institute of Molecular Biology and Microbiology Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2014.09.003 2Department

The hallmark of bubonic plague is the presence of grotesquely swollen lymph nodes, called buboes. This frenzied inflammatory response to Yersinia pestis is poorly understood. In this issue of Immunity, St. John et al. (2014) explore the mechanism by which Y. pestis spreads and thus leads to this striking lymphadenopathy. In anticipation of microbial infections, the dendritic cell (DC) acts as an early immune detection system in tissue sites. Upon encounter with a microbe, DCs quickly mature and traffic to local draining lymph nodes (dLNs), where they interact with T cells and B cells to promote the development of adaptive immunity. Simultaneously, neutrophils, monocytes, macrophages, and additional phagocytic cells infiltrate tissues and attempt to eliminate the microorganism before the adaptive response is fully engaged. After clonal expansion in LNs, lymphocytes also traffic to sites of infection to combat pathogens. Receptors and signaling molecules are involved at every step along this process

with the goal of orchestrating an effective immune response by multiple immune cells. These layers of protection appear ideally suited to stop pathogens in their tracks, but could the migration of cells involved in immune defense collaborate with the pathogen to support the progress of disease? Certainly it appears that way with HIV, in which DCs carrying intact virus traffic to LNs to deliver the microbe to a site rich in susceptible host cells. Bacterial pathogens that preferentially replicate within lymphoid tissue, such as Salmonella and Yersinia species, could also follow this model, but the cellular basis for their migration into these tissues is

poorly understood (Viboud and Bliska, 2005; Zhang et al., 2008a; Zhang et al., 2008b). In this issue of Immunity, St. John et al. (2014) show that DCs play an important role in delivering Yersinia pestis into regional LNs, whereas other phagocytic cells promote inter-LN spread and thus support disease progression of Y. pestis. The terrifying bubonic plague, responsible for the elimination of large portions of the European population during epidemic outbreaks, is a consequence of Y. pestis inoculation by infected fleas. An impressive sign of disease is the bubo, which is the result of an apparent unrestrained swelling of LNs proximal to the

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Targeting foxp1 for reinstating anticancer immunosurveillance.

Transforming growth factor β (TGF-β) is a canonical immunosuppressive cytokine secreted by tumors. In this issue of Immunity, Stephen et al. (2014) re...
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