REFERENCES

1. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers 2020;12:738.

2. Marei HE, Hasan A, Pozzoli G, Cenciarelli C. Cancer immunotherapy with immune checkpoint inhibitors (ICIs): potential, mechanisms of resistance, and strategies for reinvigorating T cell responsiveness when resistance is acquired. Cancer Cell Int 2023;23:64.

3. Pai SI, Cesano A, Marincola FM. The paradox of cancer immune exclusion: immune oncology next frontier. In: Lee PP, Marincola FM, editors. Tumor microenvironment. Cham: Springer International Publishing; 2020. pp. 173-95.

4. Gajewski TF, Corrales L, Williams J, Horton B, Sivan A, Spranger S. Cancer immunotherapy targets based on understanding the T cell-inflamed versus non-T cell-inflamed tumor microenvironment. In: Kalinski P, editor. Tumor immune microenvironment in cancer progression and cancer therapy. Cham: Springer International Publishing; 2017. pp. 19-31.

5. Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: indication, genotype, and immunotype. Immunity 2023;56:2188-205.

6. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 2017;541:321-30.

7. Clifton GT, Rothenberg M, Ascierto PA, et al. Developing a definition of immune exclusion in cancer: results of a modified Delphi workshop. J Immunother Cancer 2023;11:e006773.

8. Bagaev A, Kotlov N, Nomie K, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 2021;39:845-65.e7.

9. Salmon H, Remark R, Gnjatic S, Merad M. Host tissue determinants of tumour immunity. Nat Rev Cancer 2019;19:215-27.

10. Bu X, Mahoney KM, Freeman GJ. Learning from PD-1 resistance: new combination strategies. Trends Mol Med 2016;22:448-51.

11. Sharma A, Rudra D. Emerging functions of regulatory T cells in tissue homeostasis. Front Immunol 2018;9:883.

12. Nishikawa H, Koyama S. Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies. J Immunother Cancer 2021;9:e002591.

13. Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002;2:389-400.

14. Gershon RK, Kondo K. Infectious immunological tolerance. Immunology 1971;21:903-14.

15. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 1970;18:723-37.

16. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969;166:753-5.

17. Astarita JL, Dominguez CX, Tan C, et al. Treg specialization and functions beyond immune suppression. Clin Exp Immunol 2023;211:176-83.

18. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151-64.

19. O’Garra A, Murphy K. Role of cytokines in determining T-lymphocyte function. Curr Opin Immunol 1994;6:458-66.

20. Peng G, Li S, Wu W, Sun Z, Chen Y, Chen Z. Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection. Immunology 2008;123:57-65.

21. Apostolou I, von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 2004;199:1401-8.

22. Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G. Regulatory T cells: serious contenders in the promise for immunological tolerance in transplantation. Front Immunol 2015;6:438.

23. Jonuleit H, Schmitt E. The regulatory T cell family: distinct subsets and their interrelations. J Immunol 2003;171:6323-7.

24. Abbas AK, Benoist C, Bluestone JA, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 2013;14:307-8.

25. Hsieh CS, Lee HM, Lio CWJ. Selection of regulatory T cells in the thymus. Nat Rev Immunol 2012;12:157-67.

26. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009;30:616-25.

27. Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012;30:733-58.

28. Yano H, Andrews LP, Workman CJ, Vignali DAA. Intratumoral regulatory T cells: markers, subsets and their impact on anti-tumor immunity. Immunology 2019;157:232-47.

29. Georgiev P, Charbonnier LM, Chatila TA. Regulatory T cells: the many faces of Foxp3. J Clin Immunol 2019;39:623-40.

30. Weinberg SE, Singer BD. Toward a paradigm to distinguish distinct functions of FOXP3+ regulatory T cells. Immunohorizons 2021;5:944-52.

31. Huang L, Guo Y, Liu S, et al. Targeting regulatory T cells for immunotherapy in melanoma. Mol Biomed 2021;2:11.

32. Saison J, Demaret J, Venet F, et al. CD4+CD25+CD127- assessment as a surrogate phenotype for FOXP3+ regulatory T cells in HIV-1 infected viremic and aviremic subjects. Cytometry B Clin Cytom 2013;84B:50-4.

33. Klein S, Kretz CC, Krammer PH, Kuhn A. CD127low/- and FoxP3+ expression levels characterize different regulatory T-cell populations in human peripheral blood. J Invest Dermatol 2010;130:492-9.

34. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci 2019;110:2080-9.

35. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol 2019;16:356-71.

36. Huppert LA, Green MD, Kim L, et al. Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy. Cell Mol Immunol 2022;19:33-45.

37. Eyoh E, McCallum P, Killick J, Amanfo S, Mutapi F, Astier AL. The anthelmintic drug praziquantel promotes human Tr1 differentiation. Immunol Cell Biol 2019;97:512-8.

38. Zhao H, Liao X, Kang Y. Tregs: where we are and what comes next? Front Immunol 2017;8:1578.

39. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW. Helios expression is a marker of T cell activation and proliferation. PLoS One 2011;6:e24226.

40. Aksoylar HI, Boussiotis VA. PD-1+ Treg cells: a foe in cancer immunotherapy? Nat Immunol 2020;21:1311-2.

41. Dykema AG, Zhang J, Cheung LS, et al. Lung tumor-infiltrating Treg have divergent transcriptional profiles and function linked to checkpoint blockade response. Sci Immunol 2023;8:eadg1487.

42. Di Giorgio E, Wang L, Xiong Y, et al. MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity. J Clin Invest 2020;130:6242-60.

43. Dolsten GA, Pritykin Y. Genomic analysis of Foxp3 function in regulatory T cells. J Immunol 2023;210:880-7.

44. Trujillo-Ochoa JL, Kazemian M, Afzali B. The role of transcription factors in shaping regulatory T cell identity. Nat Rev Immunol 2023;23:842-56.

45. Obradovic A, Ager C, Turunen M, et al. Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators. Cancer Cell 2023;41:933-49.e11.

46. Rapp M, Wintergerst MWM, Kunz WG, et al. CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. J Exp Med 2019;216:1170-81.

47. Iellem A, Mariani M, Lang R, et al. Unique chemotactic response profile and specific expression of chemokine receptors Ccr4 and Ccr8 by Cd4+Cd25+ regulatory T cells. J Exp Med 2001;194:847-53.

48. Sugiyama D, Nishikawa H, Maeda Y, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A 2013;110:17945-50.

49. Sarkar T, Dhar S, Chakraborty D, et al. FOXP3/HAT1 axis controls Treg infiltration in the tumor microenvironment by inducing CCR4 expression in breast cancer. Front Immunol 2022;13:740588.

50. Medof ME, Rieder SA, Shevach EM. Disabled C3ar1/C5ar1 signaling in Foxp3+ T regulatory cells leads to TSDR demethylation and long-term stability. J Immunol 2023;211:1359-66.

51. Bayati F, Mohammadi M, Valadi M, Jamshidi S, Foma AM, Sharif-Paghaleh E. The therapeutic potential of regulatory T cells: challenges and opportunities. Front Immunol 2020;11:585819.

52. Dennis KL, Blatner NR, Gounari F, Khazaie K. Current status of interleukin-10 and regulatory T-cells in cancer. Curr Opin Oncol 2013;25:637-45.

53. Hsu P, Santner-Nanan B, Hu M, et al. IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1. J Immunol 2015;195:3665-74.

54. Konkel JE, Zhang D, Zanvit P, et al. Transforming growth factor-β signaling in regulatory T cells controls T helper-17 cells and tissue-specific immune responses. Immunity 2017;46:660-74.

55. Wan YY, Flavell RA. TGF-β and regulatory T cell in immunity and autoimmunity. J Clin Immunol 2008;28:647-59.

56. Pyzik M, Piccirillo CA. TGF-β1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukoc Biol 2007;82:335-46.

57. Chen W. TGF-β regulation of T cells. Annu Rev Immunol 2023;41:483-512.

58. Jain N, Nguyen H, Chambers C, Kang J. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci U S A 2010;107:1524-8.

59. Ledford H, Else H, Warren M. Cancer immunologists scoop medicine Nobel prize. Nature 2018;562:20-1.

60. Da M, Chen L, Enk A, Ring S, Mahnke K. The multifaceted actions of CD73 during development and suppressive actions of regulatory T cells. Front Immunol 2022;13:914799.

61. Chen S, Fan J, Zhang M, et al. CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy. Nat Commun 2019;10:150.

62. Nelson BH. IL-2, regulatory T cells, and tolerance. J Immunol 2004;172:3983-8.

63. Gasteiger G, Kastenmuller W. Foxp3+ regulatory T-cells and IL-2: the moirai of T-cell fates? Front Immunol 2012;3:179.

64. Xydia M, Rahbari R, Ruggiero E, et al. Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients. Nat Commun 2021;12:1119.

65. Fan MY, Low JS, Tanimine N, et al. Differential roles of IL-2 signaling in developing versus mature Tregs. Cell Rep 2018;25:1204-13.e4.

66. Shapiro MR, Peters LD, Brown ME, et al. Insulin-like growth factor-1 synergizes with IL-2 to induce homeostatic proliferation of regulatory T cells. J Immunol 2023;211:1108-22.

67. O’Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9:eaaa0984.

68. Wang L, Oill AT, Blanchard M, et al. Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13Rα2-targeting CAR T cells: an interim analysis. Res Sq 2023;In Press.

69. Wang H, Franco F, Tsui YC, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 2020;21:298-308.

70. Stroukov W, Mastronicola D, Albany CJ, Catak Z, Lombardi G, Scottà C. OMIP-090: a 20-parameter flow cytometry panel for rapid analysis of cell diversity and homing capacity in human conventional and regulatory T cells. Cytometry A 2023;103:362-7.

71. Santegoets SJAM, Dijkgraaf EM, Battaglia A, et al. Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. Cancer Immunol Immunother 2015;64:1271-86.

72. Mason GM, Lowe K, Melchiotti R, et al. Phenotypic complexity of the human regulatory T cell compartment revealed by mass cytometry. J Immunol 2015;195:2030-7.

73. Barcenilla H, Pihl M, Sjögren F, Magnusson L, Casas R. Regulatory T-cell phenotyping using CyTOF. In: Ono M, editor. Regulatory T-cells. New York: Springer US; 2023. pp. 231-42.

74. Jaimes MC, Leipold M, Kraker G, Amir EA, Maecker H, Lannigan J. Full spectrum flow cytometry and mass cytometry: a 32-marker panel comparison. Cytometry A 2022;101:942-59.

75. Di Giacomo AM, Santangelo F, Amato G et al. 139P - First-in-human (FIH), pharmacokinetic (PK) and pharmacodynamic (PD) study of IOA-244, a phosphoinositide 3-kinase delta (PI3K-d) inhibitor, in patients with advanced metastatic mesothelioma, uveal and cutaneous melanoma. 2021. Available from: https://www.ionctura.com/admin/resources/139pdi-giacomoioa244esmo-io-2021final.pdf. [Last accessed on 11 Jan 2024].

76. Singh U, Cui Y, Dimaano N, et al. Analytical validation of quantitative immunohistochemical assays of tumor infiltrating lymphocyte biomarkers. Biotech Histochem 2018;93:411-23.

77. Amgad M, Stovgaard ES, Balslev E, et al; International Immuno-Oncology Biomarker Working Group. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group. NPJ Breast Cancer 2020;6:16.

78. Halse H, Colebatch AJ, Petrone P, et al. Multiplex immunohistochemistry accurately defines the immune context of metastatic melanoma. Sci Rep 2018;8:11158.

79. Harms PW, Frankel TL, Moutafi M, et al. Multiplex immunohistochemistry and immunofluorescence: a practical update for pathologists. Mod Pathol 2023;36:100197.

80. Hsieh WC, Budiarto BR, Wang YF, et al. Spatial multi-omics analyses of the tumor immune microenvironment. J Biomed Sci 2022;29:96.

81. Andreatta M, Corria-Osorio J, Müller S, Cubas R, Coukos G, Carmona SJ. Interpretation of T cell states from single-cell transcriptomics data using reference atlases. Nat Commun 2021;12:2965.

82. Höllbacher B, Duhen T, Motley S, Klicznik MM, Gratz IK, Campbell DJ. Transcriptomic profiling of human effector and regulatory T cell subsets identifies predictive population signatures. Immunohorizons 2020;4:585-96.

83. Hui Z, Zhang J, Zheng Y, et al. Single-cell sequencing reveals the transcriptome and TCR characteristics of pTregs and in vitro expanded iTregs. Front Immunol 2021;12:619932.

84. Cuadrado E, van den Biggelaar M, de Kivit S, et al. Proteomic analyses of human regulatory T cells reveal adaptations in signaling pathways that protect cellular identity. Immunity 2018;48:1046-59.e6.

85. Mensink M, Schrama E, Cuadrado E, Amsen D, de Kivit S, Borst J. Proteomics reveals unique identities of human TGF-β-induced and thymus-derived CD4+ regulatory T cells. Sci Rep 2022;12:20268.

86. Duguet F, Locard-Paulet M, Marcellin M, et al. Proteomic analysis of regulatory T cells reveals the importance of themis1 in the control of their suppressive function. Mol Cell Proteomics 2017;16:1416-32.

87. Matheu MP, Othy S, Greenberg ML, et al. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun 2015;6:6219.

88. Kist de Ruijter L, van de Donk PP, Hooiveld-Noeken JS, et al. Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial. Nat Med 2022;28:2601-10.

89. Abdeladhim M, Karnell JL, Rieder SA. In or out of control: modulating regulatory T cell homeostasis and function with immune checkpoint pathways. Front Immunol 2022;13:1033705.

90. Ballman KV. Biomarker: predictive or prognostic? J Clin Oncol 2015;33:3968-71.

91. 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. Sci Rep 2015;5:15179.

92. Li L, Li Y, Yin Z, Zhu J, Yan D, Lou H. Increased frequency of regulatory T cells in the peripheral blood of patients with endometrioid adenocarcinoma. Oncol Lett 2019;18:1424-30.

93. Kolben T, Mannewitz M, Perleberg C, et al. Presence of regulatory T-cells in endometrial cancer predicts poorer overall survival and promotes progression of tumor cells. Cell Oncol 2022;45:1171-85.

94. Qiu J, Xu L, Zeng X, et al. CCL5 mediates breast cancer metastasis and prognosis through CCR5/Treg cells. Front Oncol 2022;12:972383.

95. Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 2006;107:2866-72.

96. Karagöz B, Bilgi O, Gümüs M, et al. CD8+CD28- cells and CD4+CD25+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients. Med Oncol 2010;27:29-33.

97. Erfani N, Mehrabadi SM, Ghayumi MA, et al. Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC). Lung Cancer 2012;77:306-11.

98. Hu X, Gu Y, Zhao S, Hua S, Jiang Y. Elevated circulating CD4+CD25-Foxp3+ regulatory T cells in patients with nonsmall cell lung cancer. Cancer Biother Radiopharm 2019;34:325-33.

99. Li S, Li Y, Qu X, Liu X, Liang J. Detection and significance of TregFoxP3+ and Th17 cells in peripheral blood of non-small cell lung cancer patients. Arch Med Sci 2014;10:232-9.

100. Chen C, Chen D, Zhang Y, et al. Changes of CD4+CD25+FOXP3+ and CD8+CD28- regulatory T cells in non-small cell lung cancer patients undergoing surgery. Int Immunopharmacol 2014;18:255-61.

101. Kotsakis A, Koinis F, Katsarou A, et al. Prognostic value of circulating regulatory T cell subsets in untreated non-small cell lung cancer patients. Sci Rep 2016;6:39247.

102. Luo JW, Guo YH, Wu FY, et al. Differences in immunological landscape between EGFR-mutated and wild-type lung adenocarcinoma. Dis Markers 2021;2021:3776854.

103. Sugiyama E, Togashi Y, Takeuchi Y, et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci Immunol 2020;5:eaav3937.

104. Bjoern J, Juul Nitschke N, Zeeberg Iversen T, Schmidt H, Fode K, Svane IM. Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab. Oncoimmunology 2016;5:e1100788.

105. Gambichler T, Schröter U, Höxtermann S, Susok L, Stockfleth E, Becker JC. Decline of programmed death-1-positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade. Br J Dermatol 2020;182:1214-20.

106. Pircher A, Gamerith G, Amann A, et al. Neoadjuvant chemo-immunotherapy modifies CD4+CD25+ regulatory T cells (Treg) in non-small cell lung cancer (NSCLC) patients. Lung Cancer 2014;85:81-7.

107. Koh J, Hur JY, Lee KY, et al. Regulatory (FoxP3+) T cells and TGF-β predict the response to anti-PD-1 immunotherapy in patients with non-small cell lung cancer. Sci Rep 2020;10:18994.

108. Kumagai S, Togashi Y, Kamada T, 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;21:1346-58.

109. Santagata S, Trotta AM, Rea G, et al. Abstract 6675: basal NK activity and early Tregs inhibition predicts nivolumab responsiveness in metastatic renal cancer patients (REVOLUTION) trial. Cancer Res 2020;80:6675.

110. Di Giacomo AM, Santangelo F, Amato G, et al. First-in-human (FIH) phase I study of the highly selective phosphoinositide 3-kinase inhibitor delta (PI3Kδ) inhibitor IOA-244 in patients with advanced cancer: safety, activity, pharmacokinetic (PK), and pharmacodynamic (PD) results. J Clin Oncol 2022;40:3107.

111. Kamphorst AO, Pillai RN, Yang S, et al. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A 2017;114:4993-8.

112. De Simone M, Arrigoni A, Rossetti G, et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 2016;45:1135-47.

113. Plitas G, Konopacki C, Wu K, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 2016;45:1122-34.

114. Barsheshet Y, Wildbaum G, Levy E, et al. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 2017;114:6086-91.

115. Zdanov S, Mandapathil M, Abu Eid R, et al. Mutant KRAS conversion of conventional T cells into regulatory T cells. Cancer Immunol Res 2016;4:354-65.

116. Kalvala A, Wallet P, Yang L, et al. Phenotypic switching of naïve T cells to immune-suppressive Treg-like cells by mutant KRAS. J Clin Med 2019;8:1726.

117. Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022;40:201-18.e9.

118. Wang J, Ke XY. The four types of Tregs in malignant lymphomas. J Hematol Oncol 2011;4:50.

119. Peng F, Qin Y, Mu S, Li J, Ai L, Hu Y. Prognostic role of regulatory T cells in lymphoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2020;146:3123-35.

120. Nixon AB, Schalper KA, Jacobs I, Potluri S, Wang IM, Fleener C. Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential? J Immunother Cancer 2019;7:325.

121. Ding P, Wen L, Tong F, Zhang R, Huang Y, Dong X. Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer. Cancer Drug Resist 2022;5:147-64.

122. Zang H, Peng J, Zheng H, Fan S. Hyperprogression after immune-checkpoint inhibitor treatment: characteristics and hypotheses. Front Oncol 2020;10:515.

123. Kamada T, Togashi Y, Tay C, et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A 2019;116:9999-10008.

124. Woods DM, Ramakrishnan R, Laino AS, et al. Decreased suppression and increased phosphorylated STAT3 in regulatory T cells are associated with benefit from adjuvant PD-1 blockade in resected metastatic melanoma. Clin Cancer Res 2018;24:6236-47.

125. Gadi D, Griffith A, Tyekucheva S, et al. A T cell inflammatory phenotype is associated with autoimmune toxicity of the PI3K inhibitor duvelisib in chronic lymphocytic leukemia. Leukemia 2022;36:723-32.

126. Weidner AS, Panarelli NC, Geyer JT, et al. Idelalisib-associated colitis: histologic findings in 14 patients. Am J Surg Pathol 2015;39:1661-7.

127. Manna A, Kellett T, Aulakh S, et al. Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses. Blood Adv 2020;4:2143-57.

128. Jitschin R, Braun M, Büttner M, et al. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood 2014;124:750-60.

129. Mékinian A, Quinquenel A, Belkacem KA, et al. Immuno-regulatory malignant B cells contribute to chronic lymphocytic leukemia progression. Cancer Gene Ther 2023;30:1018-28.

130. Massa M, Rosti V, Campanelli R, Fois G, Barosi G. Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia 2014;28:449-51.

131. Keohane C, Kordasti S, Seidl T, et al. JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells. Br J Haematol 2015;171:60-73.

132. Arce Vargas F, Furness AJS, Litchfield K, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 2018;33:649-63.e4.

133. Galvez-Cancino F, Simpson AP, Costoya C, et al. Fcγ receptors and immunomodulatory antibodies in cancer. Nat Rev Cancer 2024;24:51-71.

134. Chen CM, Wu WB, Chen JF, Chen Y. Characterization of the in vitro metabolites of idelalisib in liver microsomes and interspecies comparison. J Pharm Biomed Anal 2019;162:249-56.

135. Shin N, Stubbs M, Koblish H, et al. Parsaclisib is a next-generation phosphoinositide 3-kinase δ inhibitor with reduced hepatotoxicity and potent antitumor and immunomodulatory activities in models of B-cell malignancy. J Pharmacol Exp Ther 2020;374:211-22.

136. Vangapandu HV, Jain N, Gandhi V. Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs 2017;26:625-32.

137. Gadkar K, Friedrich C, Hurez V, et al. Quantitative systems pharmacology model-based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3-kinase inhibitors. CPT Pharmacometrics Syst Pharmacol 2022;11:616-27.

138. Sharma A, Subudhi SK, Blando J, et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers. Clin Cancer Res 2019;25:1233-8.

139. Retseck J, Nasr A, Lin Y, et al. Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma. J Transl Med 2018;16:184.

140. Patel TH, Brewer JR, Fan J, et al. FDA approval summary: tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. Clin Cancer Res 2023;30:269-73.

141. Lowther DE, Goods BA, Lucca LE, et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 2016;1:e85935.

142. Hong DS, Rixe O, Chiu VK, et al. Mogamulizumab in combination with nivolumab in a phase I/II study of patients with locally advanced or metastatic solid tumors. Clin Cancer Res 2022;28:479-88.

143. Kidani Y, Nogami W, Yasumizu Y, 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:e2114282119.

144. Weaver JD, Stack EC, Buggé JA, et al. Differential expression of CCR8 in tumors versus normal tissue allows specific depletion of tumor-infiltrating T regulatory cells by GS-1811, a novel Fc-optimized anti-CCR8 antibody. Oncoimmunology 2022;11:2141007.

145. Solomon I, Amann M, Goubier A, et al. CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer 2020;1:1153-66.

146. Wyant T, Frentzas S, Ahern E, et al. Abstract C033: preliminary pharmacodynamic evaluation of AU-007 in phase 1 dose escalation trial in patients with advanced solid tumors. Mol Cancer Ther 2023;22:C033.

147. Cole CB, Morelli MP, Fantini M, et al. Correction: first-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors. J Exp Clin Cancer Res 2023;42:102.

148. Le DT, Jaffee EM. Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res 2012;72:3439-44.

149. Ghiringhelli F, Menard C, Puig PE, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007;56:641-8.

150. Scurr M, Pembroke T, Bloom A, et al. Low-dose cyclophosphamide induces antitumor T-cell responses, which associate with survival in metastatic colorectal cancer. Clin Cancer Res 2017;23:6771-80.

151. Roselli M, Cereda V, di Bari MG, et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology 2013;2:e27025.

152. Revenko A, Carnevalli LS, Sinclair C, et al. Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer. J Immunother Cancer 2022;10:e003892.

153. Eschweiler S, Ramírez-Suástegui C, Li Y, et al. Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. Nature 2022;605:741-6.

154. Tarantelli C, Argnani L, Zinzani PL, Bertoni F. PI3Kδ inhibitors as immunomodulatory agents for the treatment of lymphoma patients. Cancers 2021;13:5535.

155. Scirocchi F, Scagnoli S, Botticelli A, et al. Immune effects of CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer: relief from immunosuppression is associated with clinical response. EBioMedicine 2022;79:104010.

156. Kohlhapp FJ, Haribhai D, Mathew R, et al. Venetoclax increases intratumoral effector T cells and antitumor efficacy in combination with immune checkpoint blockade. Cancer Discov 2021;11:68-79.

157. Anandappa AJ, Wu CJ, Ott PA. Directing traffic: how to effectively drive T cells into tumors. Cancer Discov 2020;10:185-97.

158. Wei T, Zhong W, Li Q. Role of heterogeneous regulatory T cells in the tumor microenvironment. Pharmacol Res 2020;153:104659.

159. Principe DR, Chiec L, Mohindra NA, Munshi HG. Regulatory T-cells as an emerging barrier to immune checkpoint inhibition in lung cancer. Front Oncol 2021;11:684098.

160. Korman AJ, Garrett-Thomson SC, Lonberg N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov 2022;21:509-28.

161. Jameson-Lee M, Luke JJ. Ipilimumab combination dosing: less is more. Clin Cancer Res 2021;27:5153-5.

162. Di Giacomo AM, Lahn M, Eggermont AM, et al. The future of targeting cytotoxic T-lymphocyte-associated protein-4: is there a role? Eur J Cancer 2023;198:113501.

163. Maio M, Blank C, Necchi A, et al. Neoadjuvant immunotherapy is reshaping cancer management across multiple tumour types: the future is now! Eur J Cancer 2021;152:155-64.

164. Peña-Asensio J, Calvo H, Torralba M, Miquel J, Sanz-de-Villalobos E, Larrubia JR. Anti-PD-1/PD-L1 based combination immunotherapy to boost antigen-specific CD8+ T cell response in hepatocellular carcinoma. Cancers 2021;13:1922.

165. Gianchecchi E, Fierabracci A. Inhibitory receptors and pathways of lymphocytes: the role of PD-1 in Treg development and their involvement in autoimmunity onset and cancer progression. Front Immunol 2018;9:2374.

166. Moore DC, Elmes JB, Shibu PA, Larck C, Park SI. Mogamulizumab: an anti-CC chemokine receptor 4 antibody for T-cell lymphomas. Ann Pharmacother 2020;54:371-9.

167. Orcutt-Jahns BT, Emmel PC, Snyder EM, Taylor SD, Meyer AS. Multivalent, asymmetric IL-2-Fc fusions show enhanced selectivity for regulatory T cells. Sci Signal 2023;16:eadg0699.

168. Fattori S, Le Roy A, Houacine J, et al. CD25high effector regulatory T cells hamper responses to PD-1 blockade in triple-negative breast cancer. Cancer Res 2023;83:3026-44.

169. Simonelli M, Garralda E, Eskens F, et al. Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study. ESMO Open 2022;7:100562.

170. Tsang K, Fantini M, Cole C, Annunziata C, Arlen P. 840 A therapeutic humanized anti-carcinoma monoclonal antibody (mAb) can also identify immunosuppressive regulatory T (Tregs) cells and down regulate Treg-mediated immunosuppression. J Immunother Cancer 2021;9:A881.

171. García-Díaz N, Wei Q, Taskén K. Small molecule inhibitors targeting regulatory T cells for cancer treatment. Eur J Immunol 2023:e2350448.

172. Li JY, Duan XF, Wang LP, et al. Selective depletion of regulatory T cell subsets by docetaxel treatment in patients with nonsmall cell lung cancer. J Immunol Res 2014;2014:286170.

173. Deng B, Yang B, Chen J, et al. Gallic acid induces T-helper-1-like Treg cells and strengthens immune checkpoint blockade efficacy. J Immunother Cancer 2022;10:e004037.

174. Marshall LA, Marubayashi S, Jorapur A, et al. Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4. J Immunother Cancer 2020;8:e000764.

175. Ketcham JM, Marshall LA, Talay O. CCR4 antagonists inhibit Treg trafficking into the tumor microenvironment. ACS Med Chem Lett 2018;9:953-5.

176. Yoshie O. CCR4 as a therapeutic target for cancer immunotherapy. Cancers 2021;13:5542.

177. Lim EL, Okkenhaug K. Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy. Immunology 2019;157:210-8.

178. Ahmad S, Abu-Eid R, Shrimali R, et al. Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of T regulatory cells to enhance cancer immunotherapy. Cancer Res 2017;77:1892-904.

179. Kirkwood JM, Iannotti N, Cho D, et al. Abstract CT176: effect of JAK/STAT or PI3Kδ plus PD-1 inhibition on the tumor microenvironment: biomarker results from a phase Ib study in patients with advanced solid tumors. Cancer Res 2018;78:CT176.

180. Borazanci E, Pishvaian MJ, Nemunaitis J, Weekes C, Huang J, Rajakumaraswamy N. A phase Ib study of single-agent idelalisib followed by idelalisib in combination with chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma. Oncologist 2020;25:e1604-13.

181. Haselmayer P, Camps M, Muzerelle M, et al. Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies. Front Immunol 2014;5:233.

182. Johnson Z, Tarantelli C, Civanelli E, et al. IOA-244 is a non-ATP-competitive, highly selective, tolerable PI3K delta inhibitor that targets solid tumors and breaks immune tolerance. Cancer Res Commun 2023;3:576-91.

183. Di Giacomo AM, Santangelo F, Amato G, et al. First-in-human (FIH) phase I dose escalation study (part A) of the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) roginolisib in patients with advanced cancer and dose confirmation in uveal melanoma (part B). J Clin Oncol 2023;41:3110.

184. Schreiber SL. The rise of molecular glues. Cell 2021;184:3-9.

185. Bonazzi S, d'Hennezel E, Beckwith REJ, et al. Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy. Cell Chem Biol 2023;30:235-47.e12.

186. Munn DH, Sharma MD, Johnson TS. Treg destabilization and reprogramming: implications for cancer immunotherapy. Cancer Res 2018;78:5191-9.

187. Dixon ML, Leavenworth JD, Leavenworth JW. Lineage reprogramming of effector regulatory T cells in cancer. Front Immunol 2021;12:717421.

188. Moreno Ayala MA, Li Z, DuPage M. Treg programming and therapeutic reprogramming in cancer. Immunology 2019;157:198-209.

189. Keller P, Mazo I, Gao Y, et al. Abstract P106: reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy. Mol Cancer Ther 2021;20:P106.

190. Naing A, Park JC, Klempner SJ, et al. 1033P First-in-human study of MALT1 inhibitor MPT-0118: results from monotherapy dose escalation in advanced or metastatic refractory solid tumors. Ann Oncol 2023;34:S627-8.

191. Perez SA, Karamouzis MV, Skarlos DV, 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;13:2714-21.

192. Gutierrez L, Jang M, Zhang T, Akhtari M, Alachkar H. Midostaurin reduces regulatory T cells markers in acute myeloid leukemia. Sci Rep 2018;8:17544.

193. Wilson KR, Villadangos JA, Mintern JD. Dendritic cell Flt3 - regulation, roles and repercussions for immunotherapy. Immunol Cell Biol 2021;99:962-71.

194. Redin E, Garmendia I, Lozano T, et al. SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation. J Immunother Cancer 2021;9:e001496.

195. Pantziarka P, Vandeborne L, Bouche G. A database of drug repurposing clinical trials in oncology. Front Pharmacol 2021;12:790952.

196. Stransky N, Ruth P, Schwab M, Löffler MW. Can any drug be repurposed for cancer treatment? A systematic assessment of the scientific literature. Cancers 2021;13:6236.

Cancer Drug Resistance
ISSN 2578-532X (Online)

Portico

All published articles will preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles will preserved here permanently:

https://www.portico.org/publishers/oae/