Regulatory T (Treg) cells reside in lymphoid organs and barrier tissues where they control different types of inflammatory responses. Treg cells are also found in human cancers, and studies in animal models suggest that they contribute to cancer progression. However, properties of human intratumoral Treg cells and those present in corresponding normal tissue remain largely unknown. Here, we analyzed features of Treg cells in untreated human breast carcinomas, normal mammary gland, and peripheral blood. Tumor-resident Treg cells were potently suppressive and their gene-expression pattern resembled that of normal breast tissue, but not of activated peripheral blood Treg cells. Nevertheless, a number of cytokine and chemokine receptor genes, most notably CCR8, were upregulated in tumor-resident Treg cells in comparison to normal tissue-resident ones. Our studies suggest that targeting CCR8 for the depletion of tumor-resident Treg cells might represent a promising immunotherapeutic approach for the treatment of breast cancer.

Bioinformatics and Genomics Programme Centre for Genomic Regulation Barcelona 08003 Spain; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry Moscow 117997 Russia

Breast Service Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Central European Institute of Technology Brno 60177 Czech Republic; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry Moscow 117997 Russia; Pirogov Russian National Research Medical University Moscow 117997 Russia

Howard Hughes Medical Institute Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA; Immunology Program Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Howard Hughes Medical Institute Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA; Immunology Program Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA; Ludwig Center at Memorial Sloan Kettering Cancer Center Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Howard Hughes Medical Institute Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA; Immunology Program Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA; Ludwig Center at Memorial Sloan Kettering Cancer Center Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA; Breast Service Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Massey Cancer Center Virginia Commonwealth University School of Medicine Richmond VA 23298 USA

Nat Rev Immunol. 2017 Jan;17(1):4-5. doi: 10.1038/nri.2016.137. PubMed

See more in PubMed

Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24:5373–5380. PubMed

Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2008;21:1527–1532. PubMed

Bolotin DA, Poslavsky S, Mitrophanov I, Shugay M, Mamedov IZ, Putintseva EV, Chudakov DM. MiXCR: software for comprehensive adaptive immunity profiling. Nature methods. 2015;12:380–381. PubMed

Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. The Journal of experimental medicine. 2013;210:2435–2466. PubMed PMC

Burzyn D, Benoist C, Mathis D. Regulatory T cells in nonlymphoid tissues. Nature immunology. 2013;14:1007–1013. PubMed PMC

Campbell DJ. Control of Regulatory T Cell Migration, Function, and Homeostasis. Journal of immunology. 2015;195:2507–2513. PubMed PMC

Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. PubMed PMC

Chaudhry A, Rudensky AY. Control of inflammation by integration of environmental cues by regulatory T cells. The Journal of clinical investigation. 2013;123:939–944. PubMed PMC

Chin Y, Janseens J, Vandepitte J, Vandenbrande J, Opdebeek L, Raus J. Phenotypic analysis of tumor-infiltrating lymphocytes from human breast cancer. Anticancer research. 1992;12:1463–1466. PubMed

Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486:549–553. PubMed PMC

Coussens LM, Pollard JW. Leukocytes in mammary development and cancer. Cold Spring Harbor perspectives in biology. 2011;3 PubMed PMC

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine. 2004;10:942–949. PubMed

Demir L, Yigit S, Ellidokuz H, Erten C, Somali I, Kucukzeybek Y, Alacacioglu A, Cokmert S, Can A, Akyol M, et al. Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs. Clinical & experimental metastasis. 2013;30:1047–1062. PubMed

DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast cancer research : BCR. 2007;9:212. PubMed PMC

Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Molecular cell. 2010;39:963–974. PubMed PMC

Faget J, Biota C, Bachelot T, Gobert M, Treilleux I, Goutagny N, Durand I, Leon-Goddard S, Blay JY, Caux C, Menetrier-Caux C. Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells. Cancer research. 2011;71:6143–6152. PubMed

Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C, Doffin AC, Durand I, Olive D, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer research. 2009;69:2000–2009. PubMed

Harner S, Noessner E, Nadas K, Leumann-Runge A, Schiemann M, Faber FL, Heinrich J, Krauss-Etschmann S. Cord blood Valpha24-Vbeta11 natural killer T cells display a Th2-chemokine receptor profile and cytokine responses. PloS one. 2011;6:e15714. PubMed PMC

Hossain DM, Panda AK, Manna A, Mohanty S, Bhattacharjee P, Bhattacharyya S, Saha T, Chakraborty S, Kar RK, Das T, et al. FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. Immunity. 2013;39:1057–1069. PubMed

Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, Debes GF, Lauber J, Frey O, Przybylski GK, et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. The Journal of experimental medicine. 2004;199:303–313. PubMed PMC

Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annual review of immunology. 2012;30:531–564. PubMed PMC

Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF, et al. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses. Immunity. 2015;43:579–590. PubMed PMC

Kim S, Lee A, Lim W, Park S, Cho MS, Koo H, Moon BI, Sung SH. Zonal difference and prognostic significance of foxp3 regulatory T cell infiltration in breast cancer. Journal of breast cancer. 2014;17:8–17. PubMed PMC

Klages K, Mayer CT, Lahl K, Loddenkemper C, Teng MW, Ngiow SF, Smyth MJ, Hamann A, Huehn J, Sparwasser T. Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Research. 2010;70:7788–7799. PubMed

Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, et al. Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. Clinical Cancer Research. 2015;21:4327–4336. PubMed

Lee JH, Kang SG, Kim CH. FoxP3+ T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues. Journal of Immunology. 2007;178:301–311. PubMed

Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nature Immunology. 2014;15:1070–1078. PubMed PMC

Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, Yin D, Gu F, Yao Z, Fu L. CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Research and Treatment. 2011;130:645–655. PubMed

Liu S, Foulkes WD, Leung S, Gao D, Lau S, Kos Z, Nielsen TO. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast cancer research : BCR. 2014;16:432. PubMed PMC

Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Current opinion in immunology. 2014;27:1–7. PubMed

Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer immunology, immunotherapy : CII. 2009;58:441–447. PubMed PMC

Pastille E, Bardini K, Fleissner D, Adamczyk A, Frede A, Wadwa M, von Smolinski D, Kasper S, Sparwasser T, Gruber AD, et al. Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer. Cancer research. 2014;74:4258–4269. PubMed

Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, Banica M, DiCioccio CB, Gross DA, Mao CA, et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003;302:1041–1043. PubMed

Roychoudhuri R, Eil RL, Restifo NP. The interplay of effector and regulatory T cells in cancer. Current opinion in immunology. 2015;33:101–111. PubMed

Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:2796–2801. PubMed PMC

Sather BD, Treuting P, Perdue N, Miazgowicz M, Fontenot JD, Rudensky AY, Campbell DJ. Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. The Journal of experimental medicine. 2007;204:1335–1347. PubMed PMC

Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, Galluzzi L, Adjemian S, Kepp O, Niso-Santano M, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science. 2012;337:1678–1684. PubMed

Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3(+) regulatory T cells in cancers: a systematic review and meta-analysis. Scientific reports. 2015;5:15179. PubMed PMC

Shugay M, Bagaev DV, Turchaninova MA, Bolotin DA, Britanova OV, Putintseva EV, Pogorelyy MV, Nazarov VI, Zvyagin IV, Kirgizova VI, et al. VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires. PLoS computational biology. 2015;11:e1004503. PubMed PMC

Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, Ezoe S, Kanakura Y, Sato E, Fukumori Y, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:17945–17950. PubMed PMC

Teng MW, Ngiow SF, von Scheidt B, McLaughlin N, Sparwasser T, Smyth MJ. Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth. Cancer research. 2010;70:7800–7809. PubMed

Ueda R. Clinical Application of Anti-CCR4 Monoclonal Antibody. Oncology. 2015;89(Suppl 1):16–21. PubMed

Xie Q, Klesney-Tait J, Keck K, Parlet C, Borcherding N, Kolb R, Li W, Tygrett L, Waldschmidt T, Olivier A, et al. Characterization of a novel mouse model with genetic deletion of CD177. Protein & cell. 2015;6:117–126. PubMed PMC

NSCLC: from tumorigenesis, immune checkpoint misuse to current and future targeted therapy

Measuring Intratumoral Heterogeneity of Immune Repertoires