The transcription factor BACH2 promotes tumor immunosuppression
Rahul Roychoudhuri, … , Luca Gattinoni, Nicholas P. Restifo
Rahul Roychoudhuri, … , Luca Gattinoni, Nicholas P. Restifo
Published January 5, 2016
Citation Information: J Clin Invest. 2016;126(2):599-604. https://doi.org/10.1172/JCI82884.
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Brief Report Oncology

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

Rahul Roychoudhuri, Robert L. Eil, David Clever, Christopher A. Klebanoff, Madhusudhanan Sukumar, Francis M. Grant, Zhiya Yu, Gautam Mehta, Hui Liu, Ping Jin, Yun Ji, Douglas C. Palmer, Jenny H. Pan, Anna Chichura, Joseph G. Crompton, Shashank J. Patel, David Stroncek, Ena Wang, Francesco M. Marincola, Klaus Okkenhaug, Luca Gattinoni, Nicholas P. Restifo

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Figure 1

BACH2 promotes immunosuppression within tumors.

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BACH2 promotes immunosuppression within tumors. (A and B) Growth of subc...
(A and B) Growth of subcutaneous (A) B16 and (B) EL-4 tumors in littermate Bach2+/+ (WT) and Bach2–/– mice at indicated time points following implantation. (A) Representative photographs of tumors at day 18 after implantation (inset). Rulers show millimeters. Error bars represent mean ± SEM. *P < 0.05; ***P < 0.005; ****P < 0.001, 2-tailed Student’s t tests. (C) Principal component analysis of transcriptional profiles from tumors of Bach2+/+ (blue) and Bach2–/– (red) mice at day 18 following implantation of B16 tumor cells. Principal component 3 is indicated by the axis perpendicular to the x and y axes. (D) Global differences in transcriptional profiles of tumors from Bach2-deficient and WT mice. 3,623 differentially expressed genes identified in the analysis (adjusted P < 0.05; fold change > 2, 2-tailed Student’s t tests) are shown. (E and F) Gene set enrichment analysis of global transcriptional differences between tumors from Bach2-deficient and WT mice. Positions of genes from indicated gene sets within a list of gene expression differences rank ordered by fold change are indicated. Kolmogorov-Smirnov statistic was used to calculate statistical significance. All data are representative of ≥2 independent experiments. NES, normalized enrichment score.