CIITA induces expression of MHC-I and MHC-II in transmissible cancers

Ong, Chrissie E. B.; Cheng, Yuanyuan; Siddle, Hannah V.; Lyons, A. Bruce; Woods, GM; Flies, Andrew S.

doi:10.1101/2021.07.14.452299

Cited by 4 publications

(3 citation statements)

References 73 publications

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“…Our results using IFN-γ expressed via a human adenovirus agree with previous studies showing that IFN-γ strongly upregulates β2m on devil facial tumour cells [6,35,36]. More recently, genetically modified DFT1 cells that either constitutively upregulate β2m or have β2m knocked out have been used to conclusively show that MHC-I is a major target in immunotherapyinduced DFT1 regressions and rare cases of natural DFT1 regressions [7,10,37,38]. Our results here using the Ad5-IFN-γ vector open the door to relatively low-cost immunotherapy to potentially treat devils with DFT1 or DFT2.…”

Section: Resultssupporting

confidence: 90%

A human adenovirus encoding IFN-γ can transduce Tasmanian devil facial tumour cells and upregulate MHC-I

Kayigwe

Darby

Lyons

et al. 2022

Preprint

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The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100%. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2, and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as vaccine platform for devils and potentially other marsupials.

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Section: Resultssupporting

confidence: 90%

A human adenovirus encoding IFN-γ can transduce Tasmanian devil facial tumour cells and upregulate MHC-I

Kayigwe

Darby

Lyons

et al. 2022

Preprint

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“…The data are provided in the electronic supplementary material [77]. Conflict of interest declaration.…”

mentioning

confidence: 99%

Class II transactivator induces expression of MHC-I and MHC-II in transmissible Tasmanian devil facial tumours

et al. 2022

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MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4 + T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine.

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“…This is hypothesized to play a key role in the absence of MHC-I on the surface of DFT1 cells. However, MHC-I can be upregulated following stimulation with interferon gamma (IFNG) (11,13,14). Subsequent studies identified MHC-I as a primary antibody target in immunotherapy-induced and rare cases of naturally occurring DFT1 tumor regression (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Automated analysis of PD1 and PDL1 in lymph nodes and the microenvironment of transmissible tumors in Tasmanian devils

Russell¹,

Palmieri

Darby³

et al. 2022

Preprint

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The wild Tasmanian devil (Sarchophilus harrisii) population has suffered a devastating decline due to two clonal transmissible cancers. Devil facial tumor 1 (DFT1) was first observed in 1996, followed by a second genetically distinct transmissible tumor, devil facial tumor 2 (DFT2), in 2014. DFT1/2 frequently metastasize, with lymph nodes being common metastatic sites. Downregulation of MHC-I by DFT1 cells is a primary means of evading allograft immunity aimed at polymorphic MHC-I proteins. DFT2 cells constitutively express MHC-I, and MHC-I is upregulated on DFT1/2 cells by interferon gamma, suggesting other immune evasion mechanisms may contribute to overcoming allograft and anti-tumor immunity. Human clinical trials have demonstrated PD1/PDL1 blockade effectively treats patients showing increased expression of PD1 in tumor draining lymph nodes, and PDL1 on peritumoral immune cells and tumor cells. The effects of DFT1/2 on systemic immunity remain largely uncharacterized. This study applied the open-access software QuPath to develop a semiautomated pipeline for whole slide analysis of stained tissue sections to quantify PD1/PDL1 expression in devil lymph nodes. The QuPath protocol provided strong correlations to manual counting. PD-1 expression was approximately 10-fold higher than PD-L1 expression in lymph nodes and was primarily expressed in germinal centers, whereas PD-L1 expression was more widely distributed throughout the lymph nodes. The density of PD1 positive cells was increased in lymph nodes containing DFT2 metastases, compared to DFT1. This suggests PD1/PDL1 exploitation may contribute to the poorly immunogenic nature of transmissible tumors in some devils and could be targeted in therapeutic or prophylactic treatments.

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CIITA induces expression of MHC-I and MHC-II in transmissible cancers

Cited by 4 publications

References 73 publications

A human adenovirus encoding IFN-γ can transduce Tasmanian devil facial tumour cells and upregulate MHC-I

A human adenovirus encoding IFN-γ can transduce Tasmanian devil facial tumour cells and upregulate MHC-I

Class II transactivator induces expression of MHC-I and MHC-II in transmissible Tasmanian devil facial tumours

Automated analysis of PD1 and PDL1 in lymph nodes and the microenvironment of transmissible tumors in Tasmanian devils

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