Evolution of a transplantable cancer by adaptation [CTVT_RNAseq_cells]
The histocompatibility barrier prevents transmission of both normal and tumour cells between individuals 1, however clonally transmissible cancers in dogs, Tasmania devils and soft-shell clams can naturally transmit as allografts 2. To understand how tumours can escape the histocompatibility barrier, we have serially passaged a mouse melanoma first into syngeneic mice and then into progressively more mismatched mouse strains until a fully allo-transplantable tumour emerged. Here we show that tumour passaging selected for cells with an anti-viral inflammatory signature, characterised by expression of MHC-I, PD-L1, Qa-1 non-classical MHC molecules and the upregulation of intergenic endogenous retroviral elements (ERVs). Knock-out of RNA sensor RIG-I 3 in the transplantable tumour cells resulted in reduced expression of MHC-I, PD-L1 and Qa-1. Antibody-mediated blockade of both PD-L1 and Qa-1 induced tumour regression after transplantation. A similar inflammatory signature was found in human melanomas that respond to anti-PD1 antibody treatment. Thus, an inflammatory anti-viral signature likely induced by RIG-I sensing of ERVs facilitates escape of the mouse melanoma from allogeneic rejection. The results underscore the immunological plasticity of melanoma and reveal an unanticipated role for inflammation in allograft immune evasion. Overall design: RNAseq profiling of YUMM1.7 tumour cells after serial passaging into mice. RNAseq was performed on polyA RNA extracted from tumour cells in vitro. Cells were obtained from dissociation of tumours and grown in vitro for 1-3 passages. Different tumours of the same passage are indicated with the letters A to H. The first batch was sequenced in January 2021 and the second batch in April 2022. The F2 tumour cells were resequenced in April 2022 for reference.