title: The transcription factor BACH2 promotes tumor immunosuppression.
abstract: The immune system has a powerful ability to recognize and kill cancer cells, but its function is often suppressed within tumors, preventing clearance of disease. Functionally diverse innate and adaptive cellular lineages either drive or constrain immune reactions within tumors. The transcription factor (TF) BACH2 regulates the differentiation of multiple innate and adaptive cellular lineages, but its role in controlling tumor immunity has not been elucidated. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. Tumor growth was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity. However, augmented tumor clearance in the absence of Bach2 was dependent upon the adaptive immune system. Analysis of tumor-infiltrating lymphocytes from Bach2-deficient mice revealed high frequencies of rapidly proliferating effector CD4+ and CD8+ T cells that expressed the inflammatory cytokine IFN-γ. Effector T cell activation coincided with a reduction in the frequency of intratumoral Foxp3+ Tregs. Mechanistically, BACH2 promoted tumor immunosuppression through Treg-mediated inhibition of intratumoral CD8+ T cells and IFN-γ. These findings demonstrate that BACH2 is a key component of the molecular program of tumor immunosuppression and identify therapeutic targets for the reversal of immunosuppression in cancer.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eil
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.forename: Francis M
authors.initials: FM
authors.lastname: Grant
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Gautam
authors.initials: G
authors.lastname: Mehta
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Pan
authors.forename: Anna
authors.initials: A
authors.lastname: Chichura
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.forename: Shashank J
authors.initials: SJ
authors.lastname: Patel
authors.forename: David
authors.initials: D
authors.lastname: Stroncek
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D007371:Interferon-gamma