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.

Treg programming and therapeutic reprogramming in cancer

“…This is due to a direct role in Tregs, where Bach2 is required to suppress inflammatory transcriptional programmes. In the absence of Bach2, Tregs reprogramme to Th1‐ and Th2‐like cells and enhance CD8 + antitumour T‐cell responses, significantly impairing cancer progression …”

“…In the absence of Bach2, Tregs reprogramme to Th1-and Th2like cells and enhance CD8 + antitumour T-cell responses, significantly impairing cancer progression. 108,109 Nr4a Three orphan nuclear receptor 4A proteins (Nur77, Nurr1 and Nor1) act in a largely redundant fashion to induce and maintain Foxp3 expression. 110 NR4A expression is increased as a direct result of the strength of TCR engagement.…”

T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function

“…These data are consistent with a role for Bach2 in limiting T cell activation and function. On the other hand, studies of bach2 -/- Tregs reveal markedly impaired chemokine receptor expression, which may explain why Bach2-deficient Tregs can still suppress effector T cells in vitro (23), but bach2 -/- Tregs fail to limit colitis in the naïve CD4 T cell transfer models of colitis (23) or infiltrate tumors (32). Thus, although bach2 -/- T cells generally exhibit enhanced effector function, loss or down-regulation of Bach2 in T cells may limit their capacity to efficiently traffic to sites of inflammation or infection.…”

Regulation of regulatory T cells in cancer

“…In human tumours, the frequency of FOXP3 + cells relative to total CD3 + T cells or CD8 + T cells is negatively correlated with survival in multiple cancer types, including renal cell carcinoma, non‐small‐cell lung carcinoma, hepatocellular carcinoma, pancreatic cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer and colorectal cancer . The frequency of Treg cells as a ratio of total CD4 + T cells can be extremely high – as high as 60–80% of total CD4 + T cells in murine orthotopic B16 tumours where Treg cells can be unambiguously defined using intranuclear Foxp3 staining . The size of Treg cell populations within tumours can be affected by a number of processes: the conversion of conventional CD4 + Foxp3 − (Tconv cells) into pTreg cells under the influence of tumour‐derived factors including TGF‐ β , recruitment of Treg cells from the periphery into tumours, the rate of proliferation and survival of recruited, peripherally induced or tissue‐resident Treg cells (Fig.…”

“…55 The frequency of Treg cells as a ratio of total CD4 + T cells can be extremely highas high as 60-80% of total CD4 + T cells in murine orthotopic B16 tumours where Treg cells can be unambiguously defined using intranuclear Foxp3 staining. 56 The size of Treg cell populations within tumours can be affected by a number of processes: the conversion of conventional CD4 + Foxp3 À (Tconv cells) into pTreg cells under the influence of tumour-derived factors including TGF-b, recruitment of Treg cells from the periphery into tumours, the rate of proliferation and survival of recruited, peripherally induced or tissue-resident Treg cells ( Fig. 1).…”