ABSTRACT
Immune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs). We utilise our existing CRC multi-region multi-omic dataset that we supplement with high-resolution spatially-resolved neoantigen sequencing data and highly multiplexed imaging of the tumour microenvironment (TME). Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes, and that SCAAs contribute to silencing of neoantigens. We observe that strong immune escape and exclusion occur at the outset of CRC formation, and that within tumours, including at the microscopic level of individual tumour glands, additional immune escape alterations have negligible consequences for the immunophenotype of cancer cells. Further minor immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak. Collectively, we show that immune evasion in CRC follows a "Big Bang" evolutionary pattern, whereby genetic, epigenetic and TME-driven immune evasion acquired by the time of transformation defines subsequent cancer-immune evolution.
ABSTRACT
Interest in spatial omics is on the rise, but generation of highly multiplexed images remains challenging, due to cost, expertise, methodical constraints, and access to technology. An alternative approach is to register collections of whole slide images (WSI), generating spatially aligned datasets. WSI registration is a two-part problem, the first being the alignment itself and the second the application of transformations to huge multi-gigapixel images. To address both challenges, we developed Virtual Alignment of pathoLogy Image Series (VALIS), software which enables generation of highly multiplexed images by aligning any number of brightfield and/or immunofluorescent WSI, the results of which can be saved in the ome.tiff format. Benchmarking using publicly available datasets indicates VALIS provides state-of-the-art accuracy in WSI registration and 3D reconstruction. Leveraging existing open-source software tools, VALIS is written in Python, providing a free, fast, scalable, robust, and easy-to-use pipeline for registering multi-gigapixel WSI, facilitating downstream spatial analyses.
Subject(s)
Microscopy , Software , Microscopy/methods , TechnologyABSTRACT
Hereditary gastrointestinal cancer is associated with molecular and neoplastic precursors which have revealed much about sporadic carcinogenesis. Therefore, an appreciation of constitutional and somatic events linked to these syndromes have provided a useful model for the development of risk models and preventative strategies. In this review, we focus of two of the best characterized syndromes, Lynch syndrome (LS) and familial adenomatous polyposis (FAP). Our understanding of the neoplasia-immune interaction in LS has contributed to the development of immune mediated therapies including cancer preventing vaccines and immunotherapy for cancer precursors. Chemoprevention in LS with aspirin and nonsteroidal anti-inflammatory drugs has also translated into clinical cancer, however the efficacy of such agents in FAP remains elusive when cancer is applied as an endpoint in trials rather than the use of 'indirect' endpoints such as polyp burden, and requires further elucidation of biological mechanisms in FAP. Finally, we review controversies in gastrointestinal surveillance for LS and FAP, including limitations and opportunities of upper and lower gastrointestinal endoscopy in the prevention and early detection of cancer.
