Targeting BCL9/BCL9L enhances CD4+ T cell-mediated Th1 antitumor immunity through activation of STAT1/STAT4 signaling

Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26:566–76.

Article  PubMed  CAS  Google Scholar 

Huang AC, Orlowski RJ, Xu X, Mick R, George SM, Yan PK, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019;25:454–61.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kubli SP, Berger T, Araujo DV, Siu LL, Mak TW. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. 2021;20:899–919.

Article  PubMed  CAS  Google Scholar 

Speiser DE, Chijioke O, Schaeuble K, Münz C. CD4+ T cells in cancer. Nat Cancer. 2023;4:317–29.

Article  PubMed  CAS  Google Scholar 

Ruterbusch M, Pruner KB, Shehata L, Pepper M. In vivo CD4+ T cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol. 2020;38:705–25.

Article  PubMed  CAS  Google Scholar 

Wang B, Hu S, Fu X, Li L. CD4+ Cytotoxic T lymphocytes in cancer immunity and immunotherapy. Adv Biol (Weinh). 2023;7:e2200169.

Article  PubMed  Google Scholar 

Oh DY, Fong L. Cytotoxic CD4+ T cells in cancer: expanding the immune effector toolbox. Immunity. 2021;54:2701–11.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kim S, Kwak JE, Koh JY, Lee JE, Kook HW, Kim M, et al. NKG2D-mediated cytotoxicity of CD4 cytotoxic T cells in multiple myeloma. Blood. 2025;146:456–70.

Article  PubMed  CAS  Google Scholar 

Cachot A, Bilous M, Liu YC, Li X, Saillard M, Cenerenti M, et al. Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer. Sci Adv. 2021;7:eabe3348.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vienot A, Jacquin M, Rebucci-Peixoto M, Pureur D, Ghiringhelli F, Assenat E, et al. Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82). BMC Cancer. 2023;23:710.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kervevan J, Chakrabarti LA. Role of CD4+ T cells in the control of viral infections: recent advances and open questions. Int J Mol Sci. 2021;22:523.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.

Article  PubMed  CAS  Google Scholar 

Gay DM, Ridgway RA, Müller M, Hodder MC, Hedley A, Clark W, et al. Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nat Commun. 2019;10:723.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W. Crystal structure of a beta-catenin/BCL9/Tcf4 complex. Mol Cell. 2006;24:293–300.

Article  PubMed  CAS  Google Scholar 

Jiang M, Kang Y, Sewastianik T, Wang J, Tanton H, Alder K, et al. BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins. Nat Commun. 2020;11:19.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Huge N, Sandbothe M, Schröder AK, Stalke A, Eilers M, Schäffer V, et al. Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma. Hepatol Int. 2020;14:373–84.

Article  PubMed  Google Scholar 

Vafaizadeh V, Buechel D, Rubinstein N, Kalathur RKR, Bazzani L, Saxena M, et al. The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis. Oncogene. 2021;40:6195–209.

Article  PubMed  PubMed Central  CAS  Google Scholar 

He F, Wu Z, Liu C, Zhu Y, Zhou Y, Tian E, et al. Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell (cDC1) activation and tumor infiltration. Signal Transduct Target Ther. 2024;9:139.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Wang X, Feng M, Xiao T, Guo B, Liu D, Liu C, et al. BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer. Oncogene. 2021;40:2982–97.

Article  PubMed  CAS  Google Scholar 

Feng M, Jin JQ, Xia L, Xiao T, Mei S, Wang X, et al. Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells. Sci Adv. 2019;5:eaau5240.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Feng M, Wu Z, Zhou Y, Wei Z, Tian E, Mei S, et al. BCL9 regulates CD226 and CD96 checkpoints in CD8+ T cells to improve PD-1 response in cancer. Signal Transduct Target Ther. 2021;6:313.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Yang F, Li A, Zhu Y, Zhou Y, Tian E, Yang M, et al. GATA1-mediated Notch signaling augment antitumor immunity of CD11b+CD27- natural killer cells maturation via BCL9/β-catenin signal. Cell Rep. 2025;44:115708.

Article  PubMed  CAS  Google Scholar 

Notani D, Gottimukkala KP, Jayani RS, Limaye AS, Damle MV, Mehta S, et al. Global regulator SATB1 recruits beta-catenin and regulates T(H)2 differentiation in Wnt-dependent manner. PLoS Biol. 2010;8:e1000296.

Article  PubMed  PubMed Central  Google Scholar 

Yu Q, Sharma A, Oh SY, Moon HG, Hossain MZ, Salay TM, et al. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma. Nat Immunol. 2009;10:992–9.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Keerthivasan S, Aghajani K, Dose M, Molinero L, Khan MW, Venkateswaran V, et al. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci Transl Med. 2014;6:225ra28.

Article  PubMed  PubMed Central  Google Scholar 

Wang B, Tian T, Kalland KH, Ke X, Qu Y. Targeting Wnt/β-Catenin signaling for cancer immunotherapy. Trends Pharmacol Sci. 2018;39:648–58.

Article  PubMed  CAS  Google Scholar 

Badia IMP, Vélez Santiago J, Braunger J, Geiss C, Dimitrov D, Müller-Dott S, et al. decoupleR: ensemble of computational methods to infer biological activities from omics data. Bioinform Adv. 2022;2:vbac016.

Article  Google Scholar 

Ceribelli M, Hou ZE, Kelly PN, Huang DW, Wright G, Ganapathi K, et al. A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell. 2016;30:764–78.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Banik S, Rakshit S, Sarkar K. The role of STAT1 in T helper cell differentiation during breast cancer progression. J Breast Cancer. 2021;24:253–65.

Article  PubMed  PubMed Central  Google Scholar 

Comments (0)

No login
gif