Biology subjects

Cheung, J. F.

Publications and source records attributed to Cheung, J. F..

4 recordsLinked to original sources

bioRxiv2021

A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy

AO_SCPLOWBSTRACTC_SCPLOWDisseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D cultures in vitro and on chicken embryo chorioallantoic membrane (CAM) in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor {beta} (RAR{beta}) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lo phenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.

cancer biology↗

bioRxiv2021

A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

"Stem-like" TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+ tumor-specific CD8+ T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from "hot" to "cold". By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSL CD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

immunology↗

bioRxiv2020

Priming of Myelin-Specific T Cells in the Absence of Dendritic Cells Results in Accelerated Development of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is predominantly mediated by pro-inflammatory CD4+ T cell responses to CNS antigens, including myelin proteolipid protein (PLP). Dendritic cells (DCs) are considered critical for inducing T cell responses against infectious agents, but the importance of DCs in priming self-reactive CD4+ T cells in autoimmune disease such as MS has been unclear. To determine the requirement of DCs in PLP-specific CD4+ T cell responses and EAE, we genetically deleted CD11c+ DCs in PLP T cell receptor (TCR) transgenic SJL mice constitutively. DC deficiency did not impair the development, selection or the pathogenic function of PLP-specific CD4+ T cells in these mice, and resulted in accelerated spontaneous EAE compared to DC sufficient controls. In addition, using a genetic approach to ablate DCs conditionally in SJL mice, we show that CD11c+ DCs were dispensable for presenting exogenous or endogenous myelin antigen to PLP-specific T cells and for promoting pro-inflammatory T cell responses and severe EAE. Our findings demonstrate that constitutive or conditional ablation of CD11c+ DCs diminished self-tolerance to PLP autoantigen. They further show that in the absence of DCs, non-DCs can efficiently present CNS myelin antigens such as PLP to self-reactive T cells, resulting in accelerated onset of spontaneous or induced EAE.

immunology↗

bioRxiv2020

NG2+/Nestin+ mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2

In the bone marrow (BM) microenvironment, NG2+/Nestin+ mesenchymal stem cells (MSCs) promote hematopoietic stem cell (HSC) quiescence1,2. Importantly, the BM can also harbour disseminated tumour cells (DTCs) from multiple cancers, which, like HSCs, can remain dormant3. The BM signals are so growth-restrictive that dormant BM DTCs can persist for years to decades only to awaken and fuel lethal metastasis3-10. The mechanisms and niche components regulating DTC dormancy remain largely unknown. Here, we reveal that periarteriolar BM-resident NG2+/Nestin+ MSCs can instruct breast cancer (BC) DTCs to enter dormancy. NG2+/Nestin+ MSCs produce TGF{beta}2 and BMP7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, which via p38-kinase result in p27-CDK inhibitor induction. Importantly, genetic depletion of the NG2+/Nestin+ MSCs or conditional knock-out of TGF{beta}2 in the NG2+/Nestin+ MSCs led to awakening and bone metastatic expansion of otherwise dormant p27+/Ki67- DTCs. Our results provide a direct proof that HSC dormancy niches control BC DTC dormancy. Given that aged NG2+/Nestin+ MSCs can lose homeostatic control of HSC dormancy, our results suggest that aging or extrinsic factors that affect the NG2+/Nestin+ MSC niche may result in a break from dormancy and BC bone relapse.

cancer biology↗