Abstract 153P
Background
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).
Methods
We leverage our existing CRC multi-region multi-omic dataset of 495 single glands (Heide et al., Nature, 2022), which we supplement with high-resolution targeted sequencing data and highly multiplexed imaging of the tumour microenvironment (TME) in 82 micro-biopsies, including the invasive margin and distant normal mucosa. We evaluate spatially-resolved normalised neoantigen burden, immune escape status, epigenetic alterations and immune infiltrate levels across and within 29 CRCs.
Results
Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes. SCAAs, together with transcriptional editing, emerge as a prevalent mechanism for silencing clonal 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, localised alterations have negligible consequences for the immunophenotype of cancer cells. Localised immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak.
Conclusions
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. Our findings suggest that epigenetic control could play a significant role in resistance to immune surveillance, and therefore epigenome modifying drugs could synergize with immunotherapy.
Legal entity responsible for the study
The authors.
Funding
Cancer Research UK, Wellcome Trust, Jean Shanks/Pathological Society, Chalmers Area of Advance Health Engineering.
Disclosure
A. Baker: Non-Financial Interests, Personal and Institutional, Ownership Interest: Patent. T. Graham: Financial Interests, Institutional, Other, Honorarium: Genentech; Non-Financial Interests, Personal and Institutional, Ownership Interest: Patent. All other authors have declared no conflicts of interest.