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Inhibition of Nr4a Receptors Enhances Anti-Tumor Immunity by Breaking Treg-Mediated Immune Tolerance

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Inhibition of Nr4a Receptors Enhances Anti-Tumor Immunity by Breaking Treg-Mediated Immune Tolerance Author Manuscript Published OnlineFirst on March 20, 2018; DOI: 10.1158/0008-5472.CAN-17-3102 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Inhibition of Nr4a receptors enhances anti-tumor immunity by breaking Treg-mediated immune tolerance Sana Hibino1, Shunsuke Chikuma1, Taisuke Kondo1, Minako Ito1, Hiroko Nakatsukasa1, Setsuko Omata-Mise1, and Akihiko Yoshimura1,2 1Department of Microbiology and Immunology, Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan 2Correspondence to: Akihiko Yoshimura, PhD Department of Microbiology and Immunology Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Phone: +81-3-5363-3483 Fax: +81-3-5360-1508 Email: [email protected] Running title: Promotion of anti-tumor immunity by Nr4a inhibition Keywords: regulatory T cell, immune tolerance, tumor immunology, transcription factors, animal models of cancer Conflict of Interest Statement: The authors declare no potential conflicts of interest. Acknowledgements: We thank N. Shiino, M. Ohkura, Y. Tokifuji, and Y. Hirata for their technical assistance. This work was supported by JSPS KAKENHI (S) 17H06175 (to A. Yoshimura), Advanced Research & Development Programs for Medical Innovation (AMED-CREST) JP17gm0510019 (to A. Yoshimura), the Takeda Science Foundation (to A. Yoshimura), the Uehara Memorial Foundation (to A. Yoshimura), the SENSHIN Medical Research Foundation (to A. Yoshimura), and Grant-in-Aid for Scientific Research on Innovative Areas 17H05801 (to S. Chikuma). 1 Downloaded from cancerres.aacrjournals.org on October 7, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2018; DOI: 10.1158/0008-5472.CAN-17-3102 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Enhanced infiltration of regulatory T (Treg) cells into tumor tissue is detrimental to cancer patients and closely associated with poor prognosis as they create an immunosuppressive state that suppresses anti-tumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg cell genetic programs, contribute to Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin (CPT) and a common cyclooxygenase-2 (COX-2) inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted anti-tumor effects. Genetic inactivation or pharmacological inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent anti-tumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacological modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment. Significance This study reveals the role of Nr4a transcription factors in Treg-mediated tolerance to anti-tumor immunity, with possible therapeutic implications for developing effective anticancer therapies. 2 Downloaded from cancerres.aacrjournals.org on October 7, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2018; DOI: 10.1158/0008-5472.CAN-17-3102 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction CD4+CD25+ regulatory T (Treg) cells, characterized by transcription factor forkhead box P3 (Foxp3) expression, play critical roles in maintaining immunological self-tolerance and homeostasis (1,2). Tregs provide dominant regulation over self-reactive conventional T cells by inhibiting their expansion and activation (3). Tumor cells are derived from self-tissues, but they could be recognized as non-self and eradicated by the immune system because of the expression of tumor-specific mutated genes. However, tumor cells with fewer immunogenic mutations are close to “self”, and likely evade immune surveillance, resulting in tumor progression. In this case, mechanisms for maintaining self-tolerance, such as Tregs, may play undesired roles by establishing immune tolerance against tumors (4,5). Additionally, tumor tissue itself creates a niche that supports survival and function of Tregs (6). An increased abundance of Tregs and a decreased ratio of intratumoral CD8+ cytotoxic T cells (CTLs) to Tregs have been shown to predict a poor prognosis in various types of human cancers (7). Tregs behave as major obstacles in clinical application of cancer immunotherapy, such as tumor vaccines or immune check point blockade (4,8). Therefore, breaking immunosuppression by Tregs is important for successful cancer therapy. Depletion of Tregs or specific disruption of Treg functions are actually thought to be promising strategies to enhance anti-tumor immunity (4,8,9). Chemical inhibitors targeting signal pathways or molecules that contribute to the suppression activities of Tregs have been intensively studied (10-13). For example, the master transcription factor Foxp3 is an attractive target, and P60, a peptide inhibitor of Foxp3, was reported to inhibit Treg function and improve tumor vaccine efficiency (14). However, there is 3 Downloaded from cancerres.aacrjournals.org on October 7, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2018; DOI: 10.1158/0008-5472.CAN-17-3102 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. not enough evidence to show that Foxp3 alone is sufficient to be targeted for disruption of Treg function because multiple factors work cooperatively with Foxp3 to maintain Treg physiology (15,16). We recently discovered that the Nr4a family of nuclear orphan receptors, consisting of three isoforms (Nr4a1, Nr4a2, and Nr4a3), redundantly play essential roles in Treg development and function via their ability to directly transactivate Foxp3 expression (17-19). Thymic Treg development was completely inhibited in mice lacking all three of the Nr4a factors on T cells (CD4-Cre Nr4a1fl/fl Nr4a2 fl/fl Nr4a3-/-), and they died within 3 weeks because of systemic multiorgan autoimmunity (18). In addition, Nr4a factors have been shown to be highly expressed on mature Foxp3+ Tregs and necessary for maintaining Treg stability and suppressive activities (19). Of note, Nr4a factors not only regulate Foxp3 expression but also globally regulate the Treg-specific transcriptional program. Therefore, Nr4a-deficient Tregs showed not only reduced expression of Foxp3, but also global dysregulation of Treg signature genes, including Foxp3-independent genes such as Ikzf4 (Eos). Thus, we hypothesize that Nr4a factors are a promising target for cancer immunotherapy to disrupt Treg function within tumors. In this study, using the mouse tumor transplantation model, we found that selective deletion of Nr4a1/Nr4a2 within Foxp3+ Tregs significantly suppressed tumor growth and induced potent anti-tumor immune responses. We then searched for pharmacological modulators of Nr4a factors, and identified two well-known drugs: the classical chemotherapeutic agent camptothecin (CPT) as the inhibitor of Nr4a transcriptional activity and cyclooxygenase (COX)-2 inhibitors, such as the celecoxib analogue SC-236, as the inhibitor of Nr4a transactivation. These drugs synergistically exerted potent anti-tumor immune responses against mouse tumor models in an Nr4a/Treg-dependent manner. We propose that Nr4a factors play important roles in Treg-mediated suppression of anti-tumor immunity, and they are attractive therapeutic targets for cancer immunotherapy. 4 Downloaded from cancerres.aacrjournals.org on October 7, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2018; DOI: 10.1158/0008-5472.CAN-17-3102 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Methods Mice All experiments using mice were approved by the Institutional Animal Care and Use Committee (IACUC; approval number 08004) of Keio University, and performed according to IACUC guidelines. The Nr4a1- and Nr4a2-floxed mice, and Foxp3YFP-Cre knock-in mice were previously described (19). C57BL/6J mice were purchased from Tokyo Laboratory Animals Science (Tokyo, Japan). IFN-γ-venus reporter mice were reported previously (20). All mice were maintained on a C57BL/6 genetic background and kept in specific pathogen-free conditions at Keio University. Cell lines and culture All cell lines were obtained between 2008-2014. Authenticated 3LL (Lewis lung carcinoma) tumor cells were obtained from the Japanese Collection of Research Bioresources (JCRB) Cell Bank (Osaka, Japan). MC38 (colon adenocarcinoma) tumor cells were kindly provided by Dr. James P. Allison. Human embryonic kidney 293T cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA USA). 3LL cells were maintained in RPMI1640 supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. MC38 and 293T cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented
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