Inducible IFN-γ Expression for MHC-I Upregulation in Devil Facial Tumor Cells

Ong, Chrissie E. B.; Lyons, A. Bruce; Woods, Gregory M.; Flies, Andrew S.

doi:10.3389/fimmu.2018.03117

Cited by 20 publications

(21 citation statements)

References 37 publications

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“…The restoration of functional MHC-I molecules without concomitant upregulation of PDL1 and SAHA-UK has multiple advantages over IFNG for triggering effective cytotoxic responses against DFT cells. First, cells transfected with NLRC5 constitutively express MHC-I and therefore do not require culturing in IFNG, which can be problematic as IFNG can also reduce cell viability 17 . Second, PDL1 negatively regulates T cell responses by inducing T cell anergy 73 and apoptosis 74 while limiting T cell activity 75 .…”

Section: Discussionmentioning

confidence: 99%

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NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers

Ong

Patchett

Darby

et al. 2020

Preprint

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Downregulation of major histocompatibility complex I (MHC-I) on tumor cells is a primary means of immune evasion by many types of cancer. Additionally, MHC-I proteins are a primary target of humoral and cellular mechanisms associated with transplant rejection. Transmissible tumors that overcome allograft rejection mechanisms and evade anti-tumor immunity have killed thousands of wild Tasmanian devils (Sarcophilus harrisii). Interferon-gamma (IFNG) upregulates surface MHC-I expression on devil facial tumor (DFT) cells but is not sufficient to induce tumor regressions. Transcriptome analysis of IFNG-treated DFT cells revealed strong upregulation of NLRC5, a master regulator of MHC-I in humans and mice. To explore the role of NLRC5 in transmissible cancers, we developed DFT cells lines that constitutively overexpress NLRC5. Transcriptomic results suggest that the role of NLRC5 as a master regulator of MHC-I is conserved in devils. Furthermore, NLRC5 was shown to drive the expression of many components of the antigen presentation pathway. To determine if MHC-I is a target of allogeneic immune responses, we tested serum from devils with natural DFT regressions against DFT cells. Antibody binding occurred with cells treated with IFNG and overexpressed NLRC5. However, CRISPR/Cas9-mediated knockout of MHC-I subunit beta-2-microglobulin (B2M) eliminated antibody binding to DFT cells. Consequently, MHC-I could be identified as a target for anti-tumor and allogeneic immunity and provides mechanistic insight into MHC-I expression and antigen presentation in marsupials. NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.

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Section: Discussionmentioning

confidence: 99%

“…PDL1 and SAHA-UK molecules can be counterproductive to the cell-mediated immune response mediated by MHC-I recognition. Additionally, the inhibition of cell proliferation and increased DFT cell death associated with IFNG 17 constrain large-scale production of IFNG-treated DFT cells for whole cell vaccines.…”

Section: Introductionmentioning

confidence: 99%

NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers

Ong

Patchett

Darby

et al. 2020

Preprint

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“…APCs, such as DCs and macrophages, play a role in the activation of acquired immune response by priming naïve T-cells to extracellular pathogens and tumors [ 3 ]. Interestingly, IFN-γ signaling was shown to be involved in this process by upregulating the expression of MHC I complex on both immune and non-immune cells, therefore facilitating the recognition of pathogen-derived antigens by effector T-cells (Teffs) [ 55 , 56 ]. More specifically, type II interferon increases IRF1 expression, which enhances the expression of MHC class I molecules by binding to the promoter region [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

Roles of IFN-γ in tumor progression and regression: a review

et al. 2020

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Background Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-γ in the tumor microenvironment (TME) may be misleading in terms of its clinical application. Main body Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-γ in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. Conclusion Significant research efforts are required to decipher IFN-γ-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-γ in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-γ responsive patients to improve their sensitivity to immuno-therapies.

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“…However, these pathways have received little attention in transmissible cancers and other naturally occurring cancers in nonmodel species ( Fig. 1 and table S1) (17)(18)(19). We have previously shown that the inhibitory immune checkpoint molecule programmed death ligand 1 (PDL1) is expressed in the DFT microenvironment and is up-regulated by interferon- (IFN-) in vitro (17).…”

Section: Introductionmentioning

confidence: 99%

A novel system to map protein interactions reveals evolutionarily conserved immune evasion pathways on transmissible cancers

et al. 2020

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Around 40% of humans and Tasmanian devils (Sarcophilus harrisii) develop cancer in their lifetime, compared to less than 10% for most species. In addition, devils are affected by two of the three known transmissible cancers in mammals. Immune checkpoint immunotherapy has transformed human medicine, but a lack of species-specific reagents has limited checkpoint immunology in most species. We developed a cut-and-paste reagent development system and used the fluorescent fusion protein system to show that immune checkpoint interactions are conserved across 160,000,000 years of evolution, CD200 is highly expressed on transmissible tumor cells, and coexpression of CD200R1 can block CD200 surface expression. The system’s versatility across species was demonstrated by fusing a fluorescent reporter to a camelid-derived nanobody that binds human programmed death ligand 1. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can be used to advance our understanding of cancer and immunological tolerance.

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Inducible IFN-γ Expression for MHC-I Upregulation in Devil Facial Tumor Cells

Abstract: Importantly, the techniques are readily transferable for testing gene function in DFT2 cells and other non-traditional species.

Cited by 20 publications

References 37 publications

NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers

NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers

Roles of IFN-γ in tumor progression and regression: a review

A novel system to map protein interactions reveals evolutionarily conserved immune evasion pathways on transmissible cancers

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