Conference Paper

EP299/#232 Genomic instability as a determinant of immune escape in ovarian cancer

To read the full-text of this research, you can request a copy directly from the authors.


Objectives Genomic instability is a hallmark of human cancer, with fundamental relevance to cancer etiology and evolution, anti-tumor immunity and therapeutic response. High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability defined by distinct mutational processes, intraperitoneal spread and tumor heterogeneity. As immunotherapies have thus far proven ineffective in HGSOC, we sought to establish the determinants of immune evasion in its natural disease history. Methods We studied the impact of mutational processes and of spatial heterogeneity on cellular phenotypes in the tumor microenvironment (TME), using genome-based stratification of homologous recombination proficient (HRP) and deficient (HRD) disease subtypes, profiling single cell phenotypes from ~1 million cells by single cell RNA sequencing, and site-matched in situ spatial imaging of 160 tumor sites obtained from 42 treatment-naive patients. Results Mutational processes in HRD-Dup (BRCA1mt-like) tumors were associated with a high neoantigen burden, cell-intrinsic JAK/STAT signaling and CD8⁺ T cell dysfunction; HRD-Del (BRCA2mt-like) tumors presented expanded M2-type macrophage populations; and foldback inversion (FBI, HRP) tumors were associated with cell-intrinsic TGFβ signaling, immune exclusion and predominantly naive T cells. HLA loss of heterozygosity was a common mechanism of immune escape in HRD tumors, connecting evolutionary selection with immune states. Multi-region sampling also revealed substantial spatial variation, highlighting the adnexa as an ‘immune-privileged’ site, and suggesting that organ microenvironments can direct immune pruning in patients with widespread disease. Conclusions Our findings yield mechanistic insights linking mutational processes in HGSOC to intra- and inter-patient variation in immune resistance, which can be leveraged to optimize future immuno-therapeutic strategies.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

ResearchGate has not been able to resolve any citations for this publication.
ResearchGate has not been able to resolve any references for this publication.