Passage of transmissible cancers in the Tasmanian devil is due to a dominant, shared peptide motif and a limited repertoire of MHC-I allotypes

Background:

Typically, cancers result from aberrant cellular growth or exposure to an oncogenic (cancer-causing) organism like the Hepatitis B virus or chemicals/radiation. Rarely, cancer passes via cancerous cells given from one individual to another (i.e is transmissible). In Tasmanian devils (a marsupial carnivore; Sacrophilus harrisii), devil facial tumour disease (DFTD), a transmissible cancer, is responsible for the rapid decline of these animals (1). The tumorous DFTD causing cells are thought to originate from Schwann cells (cells which generate myelin sheaths for peripheral axons). Two independent tumours have been identified; Devil Facial Tumour 1 (DFT1) and Devil Facial Tumour 2 (DFT2; identified in 2014; 2). They spread when one animal bites another. Ordinarily, these tumour cells should be recognised as ‘non-self’ tissue and be rejected by the immune system, however this doesn’t happen. Instead, these tumours appear to escape rejection by down-regulating or removing their surface major histocompatibility complex class 1 (MHC-1) molecules meaning T-cells fail to recognize and attack the tumour. This is not an uncommon tactic for cancerous tumours to avoid immune clearance, however for a cancer to be as transmissible as DFTD is unusual supporting other strategies allowing DFTD transmission. Here, the authors asked if the peptides displayed by the MHC-1 molecules of DFT tumours to T-cells could contribute to this transmissibility. They found Tasmania devil MHC-1 molecules can display peptides similar to host Schwann cell or neuronal cell peptides making these tumour cells appear as ‘self’.

 

Key Findings: 

1. Devil tumours have less diverse MHC-1 repertoires

Here, the authors compare MHC-1 molecules on the surface of fibroblast cells (as controls) to the DFT cell lines. To stimulate expression of MHC-1 on the surface of DFT1 tumours (which lack MHC-1 expression ordinarily), DFT1 cells are treated with yIFN. This is not needed for DFT2 tumour cells, which have surface expressed MHC-1 (2). Six MHC-1 genes have been identified in devils; Saha-UA, -UB and -UC (classical MHC-1 genes) and Saha-UD, -UK and -UM (non-classical MHC-1 genes). Only 3 variants are seen on DFT1 tumours and 5 variants on DFT2 tumours, one of which was unique to across both indicating DFT1+IFNy and DFT2 tumour cells have less MHC-1 diversity on their surfaces compared with controls.

 

2. MHC-1 from devils prefers to present 8-9 aa peptides containing hydrophobic residues

Next, the authors isolated peptide sequences bound to the heavy chain of the MHC-I molecules from their tumour and control cell lines. They identified ~25,000 unique peptides between the DFT cell lines and the fibroblast controls, ~ 1400 were shared between all cell types. Peptides are bound within the peptide binding region (PBR) of the MHC-1 molecule. Here, the authors found a preference for peptides ~8-9 amino acids long. Further analysis of the sequences of these peptides revealed a dominant motif signature. They saw these peptides preferentially contained amino acids like leucine (L) and other hydrophobic amino acids. Specifically, at position 3 (p3) and at the position p-omega (pΩ). The authors validated their findings by performing a smaller experiment to look at the peptides from DFT2 cells supporting their results. Interestingly, they show that a preference for a leucine in position p3 is more common in devil peptides when compared to those recognised by human and mouse MHC-1 molecules.

 

3. Tasmanian devils have a diverse MHC-1 B-pocket

To look in more detail at the binding pocket of the devil MHC-1 molecule, the authors compared devil MHC-1 alleles (over 16,000) and modelled devil MHC-1 using a template from the bat species Ptreopus alecto. They model using a bat template due to similarities observed at the amino acid level between bat and Tasmania devil MHC-1. This modelling analysis revealed:

1. The F-pocket of the MHC-1 molecule of Tasmania devils is largely conserved across the different devil alleles and when compared to the bat. This region contains the anchor required for docking of the hydrophobic amino acid in the pΩ position and has been documented in MHC-1 alleles from many other organisms.
2. The B-pocket of devil MHC-1 is less well conserved across different alleles and to bat MHC-1.

 

4. DFT cells can present Schwann cell peptides

If DFT cells are able to look like ‘self’ to avoid being cleared, there must have a way in which to accomplish this. By studying the origin of the peptides displayed by MHC-1 molecules on the surface of DFT cells, the authors reasoned that as DFT cells are thought to originate from Schwann cells, it is possible they may ‘mimic’ these cells by displaying similar peptides (when confronted by the immune system). Indeed, the authors found this to be the case. Four peptides were derived from nervous system proteins, including Schwann cell associated proteins.

 

What I liked about this preprint:

I have always found the concept of transmissible cancers to be very interesting. What I liked about this paper was the approach the authors took to examine the peptides bound by the MHC-1 complex to understand why DFT cells many not be recognised as ‘self’ and cleared by the immune response. Their research opens up further questions as to how tumour cells, in the wider context, may evade host immune defences. Furthermore, their work may form the basis of developing a treatment for DFTD via the use of a peptide vaccine.

 

Questions for the authors:

Q1: DFT1 tumours lack MHC-1 molecules expressed on their surface meaning they do not display peptides to the immune response. How far into the infection does the loss of MHC-1 surface expression on DFT1 tumour cells occur?

 

Q2: You show the tumour cells display similar peptides to the immune system meaning a peptide vaccine could be a solution to DFTD. However, DFTD transmission can rely on the fact the immune response to the tumours is compromised. This could have implications for vaccination against DFTD if a poor response is mounted against the inoculation. Furthermore, DFT1 cells do lack MHC-1 expression on their surface and there is evidence that DFT2 tumour cells may also follow a similar path. Can you comment on how a peptide vaccine/vaccine strategy and how this could be used for the treatment of DFTD in Tasmanian devils?

 

References:

1. McCallum, H. et al. Transmission dynamics of Tasmanian devil facial tumor disease may lead to disease-induced extinction. Ecology 90 (2009).
2. Pye, R.J. et al. A second transmissible cancer in Tasmanian devils. PNAS 113 (2016).

Tags: cancer, mhc, tasmanian devil, transmissible cancer, tumour

doi: https://doi.org/10.1242/prelights.24028

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