Rokan, Ahmed; (2025) The Evolution of a Transplantable Tumour. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

One of the hallmarks of cancer is the ability to evade the immune system. Remarkably, there are non-human cancers that can be transmitted across individuals irrespective of the histocompatibility barrier. A well-known example is the Canine Transmissible Venereal Tumour (CTVT), which is a contagious mammalian clonal allograft. To understand how a mammalian cancer might evolve the ability to escape allogeneic recognition, we have passaged a genetically well-characterised mouse melanoma cell line from syngeneic mice (C57BL/6) into progressively more allogeneic mouse crosses and eventually into fully haplotype mismatched BALB/c mice. At each passage, we performed flow cytometry analysis on dissociated tumours to characterise the host intratumoural immune infiltrate and performed RNA-seq analysis on the isolated tumour cells to obtain a more comprehensive view of the evolution of these tumours. Multiple passaging rounds resulted in a stepwise adaptation of the tumours to evade allogeneic recognition, eventually permitting their tolerance in fully mismatched mice. Flow cytometry showed greater immune infiltration in the earlier passages, including CD8+ and NK cells which, however, were unable to reject the tumour. In the later passages, CD8+ T cells were significantly reduced, while Dendritic Cells (DCs) increased. RNA-seq data on isolated tumour cells demonstrated changes in gene expression during passaging characterised by higher expression of inflammatory and antiviral markers and overexpression of intergenic Endogenous Retrotransposable Elements (RTE), MHC-I, PD-L1, and non-classical MHC molecule Qa-1. MHC-I, PD-L1, and Qa-1 expression were all decreased in transplantable tumour cells when the RNA sensor RIG-I was knocked out. Following transplantation, antibody-mediated inhibition of both PD-L1 and Qa-1 caused tumour regression. These data demonstrate that our experimental model can successfully evolve tumours that bypass the histocompatibility barrier. Our model will provide new mechanistic insights into allograft tolerance that may be used to blunt organ transplant rejection.

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