Neoadjuvant immune checkpoint blockade triggers persistent and systemic T_reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors

References

• Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong A, et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Annal Oncol. 2019;30(3):405–16. published Online First: 2018/11/27. doi:10.1093/annonc/mdy518.
   PubMed Web of Science ®Google Scholar
• Voorwerk L, Slagter M, Horlings HM, Sikorska K, van de Vijver KK, de Maaker M, Nederlof I, Kluin RJC, Warren S, Ong S, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019;25(6):920–928. published Online First: 2019/05/16. doi:10.1038/s41591-019-0432-4.
   PubMed Web of Science ®Google Scholar
• Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im S-A, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817–1828. published Online First: 2020/12/07. doi:10.1016/s0140-6736(20)32531-9.
   PubMed Web of Science ®Google Scholar
• Maio M, Blank C, Necchi A, Di Giacomo AM, Ibrahim R, Lahn M, Fox BA, Bell RB, Tortora G, Eggermont AMM. Neoadjuvant immunotherapy is reshaping cancer management across multiple tumour types: the future is now! Eur J Cancer. 2021;152:155–164. doi:10.1016/j.ejca.2021.04.035. published Online First: 20210606.
   PubMed Web of Science ®Google Scholar
• Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, Lopez-Yurda M, Grootscholten C, Beets GL, Snaebjornsson P, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566–576. published Online First: 2020/04/07. doi:10.1038/s41591-020-0805-8.
   PubMed Web of Science ®Google Scholar
• Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, Krijgsman O, van den Braber M, Philips D, Broeks A, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24(11):1655–1661. published Online First: 2018/10/10. doi:10.1038/s41591-018-0198-0.
   PubMed Web of Science ®Google Scholar
• Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556–567. doi:10.1056/NEJMoa2112651.
   PubMed Web of Science ®Google Scholar
• Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090–1100. published Online First: 20200920. doi:10.1016/S0140-6736(20)31953-X.
   PubMed Web of Science ®Google Scholar
• Loibl S, Schneeweiss A, Huober J, Braun M, Rey J, Blohmer J-U, Furlanetto J, Zahm D-M, Hanusch C, Thomalla J, et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann Oncol. 2022;33(11):1149–1158. published Online First: 20220809. doi:10.1016/j.annonc.2022.07.1940.
   PubMed Web of Science ®Google Scholar
• Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, Gherardini PF, Prestwood TR, Chabon J, Bendall SC, et al. Systemic immunity is required for effective cancer immunotherapy. Cell. 2017;168(3):487–502.e15. published Online First: 20170119. doi:10.1016/j.cell.2016.12.022.
   PubMed Web of Science ®Google Scholar
• Fransen MF, Schoonderwoerd M, Knopf P, Camps MGM, Hawinkels LJAC, Kneilling M, van Hall T, Ossendorp F. Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. JCI Insight. 2018;3(23). published Online First: 20181206. doi:10.1172/jci.insight.124507.
   PubMed Web of Science ®Google Scholar
• Garner H, de Visser KE. Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat Rev Immunol. 2020;20(8):483–497. doi:10.1038/s41577-019-0271-z. published Online First: 20200205.
   PubMed Web of Science ®Google Scholar
• Plitas GY, Rudensky AY. Regulatory T cells in cancer. Annu Rev Cancer Biol. 2020;4(1):459–477. doi:10.1146/annurev-cancerbio-030419-033428.
   Google Scholar
• Kos K, de Visser KE. The multifaceted role of regulatory T cells in breast cancer. Annu Rev Cancer Biol. 2021 published Online First: 2021/10/12;5(1):291–310. doi:10.1146/annurev-cancerbio-042920-104912.
   PubMedGoogle Scholar
• Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva E, Chudakov D, Rudensky A. Regulatory T cells exhibit distinct features in Human Breast Cancer. Immunity. 2016;45(5):1122–1134. doi:10.1016/j.immuni.2016.10.032.
   PubMed Web of Science ®Google Scholar
• 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 Res. 2014 published Online First: 20140906;16(5):432. doi:10.1186/s13058-014-0432-8.
   PubMed Web of Science ®Google Scholar
• Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med. 2013 published Online First: 2013/10/16;210(11):2435–2466. doi:10.1084/jem.20130762.
   PubMed Web of Science ®Google Scholar
• Clark NM, Martinez LM, Murdock S, deLigio JT, Olex AL, Effi C, Dozmorov MG, Bos PD. Regulatory T cells support breast cancer progression by opposing IFN-γ-dependent functional reprogramming of Myeloid Cells. Cell Rep. 2020 published Online First: 2020/12/10;33(10):108482. doi:10.1016/j.celrep.2020.108482.
   PubMed Web of Science ®Google Scholar
• Decker T, Fischer G, Bücke W, Bücke P, Stotz F, Grüneberger A, Gropp-Meier M, Wiedemann G, Pfeiffer C, Peschel C, et al. Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer. J Cancer Res Clin Oncol. 2012;138(11):1945–1950. published Online First: 20120704. doi:10.1007/s00432-012-1258-3.
   PubMed Web of Science ®Google Scholar
• Perez SA, Karamouzis MV, Skarlos DV, Ardavanis A, Sotiriadou NN, Iliopoulou EG, Salagianni ML, Orphanos G, Baxevanis CN, Rigatos G, et al. CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin Cancer Res. 2007;13(9):2714–2721. doi:10.1158/1078-0432.ccr-06-2347.
   PubMed Web of Science ®Google Scholar
• Wang L, Simons DL, Lu X, Tu TY, Solomon S, Wang R, Rosario A, Avalos C, Schmolze D, Yim J, et al. Connecting blood and intratumoral T(reg) cell activity in predicting future relapse in breast cancer. Nat Immunol. 2019;20(9):1220–1230. published Online First: 20190708. doi:10.1038/s41590-019-0429-7.
   PubMed Web of Science ®Google Scholar
• Jiang D, Gao Z, Cai Z, Wang M, He J. Clinicopathological and prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients with breast cancer: a meta-analysis. BMC Cancer. 2015 published Online First: 20151017;15(1):727. doi:10.1186/s12885-015-1742-7.
   PubMedGoogle Scholar
• Núñez NG, Tosello Boari J, Ramos RN, Richer W, Cagnard N, Anderfuhren CD, Niborski LL, Bigot J, Meseure D, De La Rochere P, et al. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients. Nat Commun. 2020;11(1):3272. published Online First: 20200629. doi:10.1038/s41467-020-17046-2.
   PubMed Web of Science ®Google Scholar
• van Pul KM, Vuylsteke R, van de Ven R, van Pul KM, van de Ven R, Te Velde EA, Rutgers EJT, van den Tol PM, Stockmann HBAC, de Gruijl TD. Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node. J ImmunoTher Cancer. 2019 published Online First: 20190522;7(1):133. doi:10.1186/s40425-019-0605-1.
   PubMedGoogle Scholar
• Kos K, Aslam MA, van de Ven R, Wellenstein MD, Pieters W, van Weverwijk A, Duits DEM, van Pul K, Hau C-S, Vrijland K, et al. Tumor-educated T(regs) drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche. Cell Rep. 2022;38(9):110447. doi:10.1016/j.celrep.2022.110447.
   PubMed Web of Science ®Google Scholar
• Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 published Online First: 2013/07/31;39(1):1–10. doi:10.1016/j.immuni.2013.07.012.
   PubMed Web of Science ®Google Scholar
• Montler R, Bell RB, Thalhofer C, Leidner R, Feng Z, Fox BA, Cheng AC, Bui TG, Tucker C, Hoen H, et al. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. Clin Transl Immunol. 2016;5(4):e70. published Online First: 20160415. doi:10.1038/cti.2016.16.
   PubMed Web of Science ®Google Scholar
• Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin Y-T, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40(2):201–18.e9. published Online First: 20220128. doi:10.1016/j.ccell.2022.01.001.
   PubMed Web of Science ®Google Scholar
• Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, Vitaly K, Itahashi K, Maeda Y, Matsui S, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. 2020;21(11):1346–1358. published Online First: 2020/09/02. doi:10.1038/s41590-020-0769-3.
   PubMed Web of Science ®Google Scholar
• Kavanagh B, O’Brien S, Lee D, et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood. 2008;112(4):1175–1183. published Online First: 2008/06/05. doi:10.1182/blood-2007-11-125435.
   PubMed Web of Science ®Google Scholar
• Sharma A, Subudhi SK, Blando J, Scutti J, Vence L, Wargo J, Allison JP, Ribas A, Sharma P. Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers. Clin Cancer Res. 2019 published Online First: 2018/07/29;25(4):1233–1238. doi:10.1158/1078-0432.CCR-18-0762.
   PubMed Web of Science ®Google Scholar
• Huang AC, Orlowski RJ, Xu X, Mick R, George SM, Yan PK, Manne S, Kraya AA, Wubbenhorst B, Dorfman L, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019;25(3):454–461. published Online First: 2019/02/26. doi:10.1038/s41591-019-0357-y.
   PubMed Web of Science ®Google Scholar
• Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al. PD-1 + regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A. 2019;116(20):9999–10008. published Online First: 2019/04/28. doi:10.1073/pnas.1822001116.
   PubMed Web of Science ®Google Scholar
• Taylor NA, Vick SC, Iglesia MD, Brickey WJ, Midkiff BR, McKinnon KP, Reisdorf S, Anders CK, Carey LA, Parker JS, et al. Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer. J Clin Invest. 2017;127(9):3472–3483. published Online First: 20170821. doi:10.1172/jci90499.
   PubMed Web of Science ®Google Scholar
• Solomon I, Amann M, Goubier A, Arce Vargas F, Zervas D, Qing C, Henry JY, Ghorani E, Akarca AU, Marafioti T, et al. CD25-T(reg)-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer. 2020;1(12):1153–1166. published Online First: 20201109. doi:10.1038/s43018-020-00133-0.
   PubMedGoogle Scholar
• Jin Y, An X, Mao B, Sun R, Kumari R, Chen X, Shan Y, Zang M, Xu L, Muntel J, et al. Different syngeneic tumors show distinctive intrinsic tumor-immunity and mechanisms of actions (MOA) of anti-PD-1 treatment. Sci Rep. 2022;12(1):3278. published Online First: 20220228. doi:10.1038/s41598-022-07153-z.
   PubMed Web of Science ®Google Scholar
• Van Damme H, Dombrecht B, Kiss M, Roose H, Allen E, Van Overmeire E, Kancheva D, Martens L, Murgaski A, Bardet PMR, et al. Therapeutic depletion of CCR8 + tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy. J ImmunoTher Cancer. 2021;9(2):e001749. doi:10.1136/jitc-2020-001749.
   PubMed Web of Science ®Google Scholar
• Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10(5):437–449. published Online First: 2006/11/14. doi:10.1016/j.ccr.2006.09.013.
   PubMed Web of Science ®Google Scholar
• Doornebal CW, Klarenbeek S, Braumuller TM, Klijn CN, Ciampricotti M, Hau C-S, Hollmann MW, Jonkers J, de Visser KE. A preclinical mouse model of invasive lobular breast cancer metastasis. Cancer Res. 2013 published Online First: 2012/11/16;73(1):353–363. doi:10.1158/0008-5472.CAN-11-4208.
   PubMed Web of Science ®Google Scholar
• Blomberg OS, Spagnuolo L, Garner H. IL-5-producing CD4(+) T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer. Cancer Cell. 2023;41(1):106–23.e10. published Online First: 20221215. doi:10.1016/j.ccell.2022.11.014.
   PubMed Web of Science ®Google Scholar
• Tavares MC, Sampaio CD, Lima GE, Andrade VP, Gonçalves DG, Macedo MP, Cordeiro de Lima VC. A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma. BMC Cancer. 2021 published Online First: 2021/08/08;21(1):901. doi:10.1186/s12885-021-08636-4.
   PubMed Web of Science ®Google Scholar
• Wellenstein MD, Coffelt SB, Duits DEM, van Miltenburg MH, Slagter M, de Rink I, Henneman L, Kas SM, Prekovic S, Hau C-S, et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature. 2019;572(7770):538–542. published Online First: 20190731. doi:10.1038/s41586-019-1450-6.
   PubMed Web of Science ®Google Scholar
• Annunziato S, Kas SM, Nethe M, Yücel H, Del Bravo J, Pritchard C, Bin Ali R, van Gerwen B, Siteur B, Drenth AP, et al. Modeling invasive lobular breast carcinoma by CRISPR/Cas9-mediated somatic genome editing of the mammary gland. Gen Devel. 2016;30(12):1470–1480. doi:10.1101/gad.279190.116.
   PubMed Web of Science ®Google Scholar
• Voorwerk L Isaeva OI, Horlings HM, Balduzzi S, Chelushkin M, Bakker NAM, Champanhet E, Garner H, Sikorska K, Loo CE, et al. PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial. Nat Cancer. 2023 Apr 10. doi:10.1038/s43018-023-00542-x. Epub ahead of print. PMID: 37038006.
   PubMedGoogle Scholar
• Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8(2):191–197. doi:10.1038/ni1428. published Online First: 20061130.
   PubMed Web of Science ®Google Scholar
• Wang S, Shen H, Bai B, Wu J, Wang J. Increased CD4+CD8+ Double-Positive T Cell in Patients with Primary Sjögren’s Syndrome Correlated with Disease Activity. J Immunol Res. 2021;2021:6658324. doi:10.1155/2021/6658324. published Online First: 2021/06/08.
   PubMed Web of Science ®Google Scholar
• Desfrancois J, Moreau-Aubry A, Vignard V, Godet Y, Khammari A, Dréno B, Jotereau F, Gervois N. Double Positive CD4CD8 αβ T Cells: a New Tumor-Reactive Population in Human Melanomas. Plos One. 2010 published Online First: 2010/01/07;5(1):e8437. doi:10.1371/journal.pone.0008437.
   PubMed Web of Science ®Google Scholar
• Schad SE, Chow A, Mangarin L, Pan H, Zhang J, Ceglia N, Caushi JX, Malandro N, Zappasodi R, Gigoux M, et al. Tumor-induced double positive T cells display distinct lineage commitment mechanisms and functions. J Exp Med. 2022;219(6): published Online First: 2022/05/24. doi: 10.1084/jem.20212169.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486–499. doi:10.1038/nri3862.
   PubMed Web of Science ®Google Scholar
• Inozume T, Hanada K, Wang QJ, Ahmadzadeh M, Wunderlich JR, Rosenberg SA, Yang JC. Selection of CD8+PD-1+ lymphocytes in fresh human melanomas enriches for tumor-reactive T cells. J Immunother (1991). 2010;33(9):956–964. doi:10.1097/CJI.0b013e3181fad2b0.
   PubMed Web of Science ®Google Scholar
• Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME, et al. PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124(5):2246–2259. published Online First: 20140325. doi:10.1172/JCI73639.
   PubMed Web of Science ®Google Scholar
• Simon SCS, Hu X, Panten J, Grees M, Renders S, Thomas D, Weber R, Schulze TJ, Utikal J, Umansky V. Eosinophil accumulation predicts response to melanoma treatment with immune checkpoint inhibitors. Oncoimmunology. 2020 published Online First: 2020/03/03;9(1):1727116. doi:10.1080/2162402X.2020.1727116.
   PubMed Web of Science ®Google Scholar
• Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hämmerling GJ. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol. 2015 published Online First: 2015/04/29;16(6):609–617. doi:10.1038/ni.3159.
   PubMed Web of Science ®Google Scholar
• Zheng X, Zhang N, Qian L, Wang X, Fan P, Kuai J, Lin S, Liu C, Jiang W, Qin S, et al. CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils. Int J Cancer. 2020;146(6):1730–1740. published Online First: 2019/12/17. doi:10.1002/ijc.32829.
   PubMed Web of Science ®Google Scholar
• Binnewies M, Mujal AM, Pollack JL, Combes AJ, Hardison EA, Barry KC, Tsui J, Ruhland MK, Kersten K, Abushawish MA, et al. Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4(+) T Cell Immunity. Cell. 2019;177(3):556–71 e16. published Online First: 2019/04/09. doi:10.1016/j.cell.2019.02.005.
   PubMed Web of Science ®Google Scholar
• Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau C-S, Verstegen NJM, Ciampricotti M, Hawinkels LJAC, Jonkers J, et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522(7556):345–348. published Online First: 20150330. doi:10.1038/nature14282.
   PubMed Web of Science ®Google Scholar
• Li H, van der Merwe PA, Sivakumar S, van der Merwe PA. Biomarkers of response to PD-1 pathway blockade. Br J Cancer. 2022 published Online First: 2022/03/02;126(12):1663–1675. doi:10.1038/s41416-022-01743-4.
   PubMed Web of Science ®Google Scholar
• Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J ImmunoTher Cancer. 2019;7(1):278. doi:10.1186/s40425-019-0768-9. published Online First: 2019/10/28.
   PubMed Web of Science ®Google Scholar
• Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020;11:583084. doi:10.3389/fimmu.2020.583084. published Online First: 2020/12/29.
   PubMed Web of Science ®Google Scholar
• Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol. 2014 published Online First: 2014/09/30;15(11):1070–1078. doi:10.1038/ni.3004.
   PubMed Web of Science ®Google Scholar
• Liu J, Blake SJ, Harjunpaa H, Fairfax KA, Yong MCR, Allen S, Kohrt HE, Takeda K, Smyth MJ, Teng MWL. Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer. Cancer Res. 2016 published Online First: 2016/08/10;76(18):5288–5301. doi:10.1158/0008-5472.CAN-16-0194.
   PubMed Web of Science ®Google Scholar
• Hollande C, Boussier J, Ziai J, Nozawa T, Bondet V, Phung W, Lu B, Duffy D, Paradis V, Mallet V, et al. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nat Immunol. 2019;20(3):257–264. published Online First: 2019/02/20. doi:10.1038/s41590-019-0321-5.
   PubMed Web of Science ®Google Scholar
• Zhang F, Parayath NN, Ene CI, Stephan SB, Koehne AL, Coon ME, Holland EC, Stephan MT. Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers. Nat Commun. 2019 published Online First: 2019/09/05;10(1):3974. doi:10.1038/s41467-019-11911-5.
   PubMed Web of Science ®Google Scholar
• Akuthota P, Wang H, Weller PF. Eosinophils as antigen-presenting cells in allergic upper airway disease. Curr Opin Allergy Clin Immunol. 2010;10(1):14–19. doi:10.1097/ACI.0b013e328334f693. published Online First: 2009/12/02.
   PubMed Web of Science ®Google Scholar
• House IG, Savas P, Lai J, Chen AXY, Oliver AJ, Teo ZL, Todd KL, Henderson MA, Giuffrida L, Petley EV, et al. Macrophage-Derived CXCL9 and CXCL10 are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade. Clin Cancer Res. 2020;26(2):487–504. published Online First: 2019/10/23. doi:10.1158/1078-0432.CCR-19-1868.
   PubMed Web of Science ®Google Scholar
• Salvagno C, Ciampricotti M, Tuit S, Hau C-S, van Weverwijk A, Coffelt SB, Kersten K, Vrijland K, Kos K, Ulas T, et al. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response. Nat Cell Biol. 2019;21(4):511–521. published Online First: 20190318. doi:10.1038/s41556-019-0298-1.
   PubMed Web of Science ®Google Scholar
• Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, Nair VS, Xu Y, Khuong A, Hoang CD, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938–945. published Online First: 20150720. doi:10.1038/nm.3909.
   PubMed Web of Science ®Google Scholar
• Kim IS, Gao Y, Welte T, Wang H, Liu J, Janghorban M, Sheng K, Niu Y, Goldstein A, Zhao N, et al. Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms. Nat Cell Biol. 2019;21(9):1113–1126. published Online First: 20190826. doi:10.1038/s41556-019-0373-7.
   PubMed Web of Science ®Google Scholar
• Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, Paulos CM. When worlds collide: th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 2018 published Online First: 20180321;15(5):458–469. doi:10.1038/s41423-018-0004-4.
   PubMed Web of Science ®Google Scholar
• Tarantino P, Corti C, Schmid P, Cortes J, Mittendorf EA, Rugo H, Tolaney SM, Bianchini G, Andrè F, Curigliano G. Immunotherapy for early triple negative breast cancer: research agenda for the next decade. NPJ Breast Cancer. 2022 published Online First: 20220218;8(1):23. doi:10.1038/s41523-022-00386-1.
   PubMed Web of Science ®Google Scholar
• Yofe I, Landsberger T, Yalin A, Solomon I, Costoya C, Demane DF, Shah M, David E, Borenstein C, Barboy O, et al. Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through FcγR engagement and type I interferon signaling. Nat Cancer. 2022;3(11):1336–1350. published Online First: 20221027. doi:10.1038/s43018-022-00447-1.
   PubMedGoogle Scholar
• Marangoni F, Zhakyp A, Corsini M, Geels SN, Carrizosa E, Thelen M, Mani V, Prüßmann JN, Warner RD, Ozga AJ, et al. Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop. Cell. 2021;184(15):3998–4015 e19. published Online First: 2021/06/23. doi:10.1016/j.cell.2021.05.027.
   PubMed Web of Science ®Google Scholar
• Kidani Y, Nogami W, Yasumizu Y, Kawashima A, Tanaka A, Sonoda Y, Tona Y, Nashiki K, Matsumoto R, Hagiwara M, et al. CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory. Proc Natl Acad Sci U S A. 2022;119(7): published Online First: 2022/02/11. doi: 10.1073/pnas.2114282119.
   PubMed Web of Science ®Google Scholar
• Kos K, van Baalen M, Meijer DA, et al. Flow cytometry-based isolation of tumor-associated regulatory T cells and assessment of their suppressive potential. Methods Enzymol. 2020;632:259–281. doi:10.1016/bs.mie.2019.07.035. published Online First: 2020/02/01.
   PubMed Web of Science ®Google Scholar
• Love MI, Huber W, Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
   Google Scholar
• pandas-dev/pandas: Pandas (v2.0.0rc1). Zenodo. [program], 2023.
   Google Scholar
• McKinney W Data structure for statistical computing in python. Proceedings of the 9th python in science conference, Austin, Texas, USA, 2010.
   Google Scholar
• Waskom ML. Seaborn: statistical data visualization. J Open Source Softw. 2021;6(60):3021. doi:https://doi.org/10.21105/joss.03021.
   Google Scholar
• Hunter JD. Matplotlib: a 2D Graphics Environment. Comput Sci Eng. 2007;9(3):90–95. doi:10.1109/MCSE.2007.55.
   Web of Science ®Google Scholar
• trevismd/statannotations: v0.5 (v0.5). Zenodo. [program], 2022.
   Google Scholar