Ovarian cancer mutational processes drive site-specific immune evasion

Authors

Vazquez-Garcia I

Uhlitz F

Ceglia N

Lim JLP

Wu M

Shah SP

Zamarin D

Doi

10.1038/s41586-022-05496-1

PMID: 36517593 · DOI: 10.1038/s41586-022-05496-1 · Journal: Nature (2022)

TL;DR

An integrative multi-omic study of 160 tumour sites from 42 treatment-naive high-grade serous ovarian cancer (HGSOC) patients combining whole-genome sequencing, single-cell RNA sequencing, digital histopathology, and multiplexed immunofluorescence. The study demonstrates that distinct mutational processes (HRD-Dup/BRCA1-like, HRD-Del/BRCA2-like, foldback-inversion/FBI) and anatomical site of disease jointly determine tumour microenvironment composition, immune cell phenotypic states, and mechanisms of immune evasion.

Cohort & data

Key findings

  • Mutational signature inference classified tumours into 16 HRD-Dup (BRCA1 mutant-like), 6 HRD-Del (BRCA2 mutant-like), and 14 FBI (foldback-inversion) cases.
  • HRD-Dup and HRD-Del tumours harbour inflammatory JAK-STAT signalling and ongoing immunoediting, reflected in loss of HLA diversity and infiltration by highly differentiated dysfunctional CD8+ T cells.
  • FBI tumours exhibit elevated immunosuppressive TGFbeta signalling, immune exclusion, and predominantly naive/stem-like and memory T cells.
  • Phenotypic state associations are site-specific: adnexal sites show enrichment of dysfunctional T cells, while non-adnexal/metastatic sites show naive/memory T cell enrichment.
  • Clonal 6p LOH (HLA loss) is primarily observed in HRD-Dup cases (31% of BRCA1-mutant cases in the validation cohort, n=1,298), representing early immune-mediated evolutionary selection.
  • Cancer cell-intrinsic JAK-STAT signalling correlates with T cell JAK-STAT activation in matched samples (R=0.62, P < 2.2e-16).
  • Spatial analysis shows CD8+PD-1+ T cells within 30 um of PD-L1+ cancer cells are common in HRD-Dup but rare/absent in FBI tumours.
  • TGFbeta signalling in FBI cases is more prominent in non-adnexal (metastatic) sites (P < 1e-4), linking FBI-specific TGFbeta to the metastatic process.

Genes & alterations

  • BRCA1 – germline/somatic mutations define HRD-Dup subtype with tandem duplications; 36/116 patients with LOH in any HLA class I gene in validation cohort
  • BRCA2 – germline/somatic mutations define HRD-Del subtype with interstitial deletions; 16/81 patients with HLA LOH
  • TP53 – nearly ubiquitous mutation in HGSOC (background alteration)
  • CCNE1 – high-level amplification associated with FBI signature; 29/118 patients with HLA LOH in validation cohort
  • CDK12 – mutations associated with tandem duplicator (TD) phenotype
  • MYC – amplification associated with expected gene dosage effects
  • CD274 (PD-L1) – upregulated expression in HRD tumours (Cancer.cell.3 cluster), upregulated in adnexal HRD-Dup tumours (P=2.8e-3)
  • PDCD1 (PD-1) – marks antigen-experienced T cells; higher co-expression with CD274 in HRD subtypes
  • HLA-A, HLA-B, B2M – MHC class I genes highly expressed in Cancer.cell.3 cluster; subject to LOH-mediated loss in 6p as immune escape mechanism

Clinical implications

  • Immunotherapies (immune checkpoint blockade) have had limited efficacy in HGSOC; this study reveals that mechanisms of immune resistance differ by mutational subtype, arguing against one-size-fits-all immunotherapy approaches.
  • HRD-Dup tumours show active immunoediting (dysfunctional T cells, PD-L1 upregulation, HLA LOH), suggesting potential responsiveness to PD-1/PD-L1 checkpoint blockade but with concurrent immune escape via HLA loss.
  • FBI tumours are immunologically “inert” with TGFbeta-mediated immune exclusion, implying that checkpoint blockade alone is unlikely to be effective; strategies to overcome TGFbeta-mediated exclusion may be needed.
  • Anatomical site heterogeneity within patients means therapeutic approaches must account for site-specific immune microenvironments; single-biopsy sampling may not represent disease-wide immune states.
  • Early detection before peritoneal dissemination is highlighted as an urgent clinical need given the high intra-patient heterogeneity.

Limitations & open questions

  • No clinical outcome or treatment response data; associations between mutational signatures and immunotherapy response are inferred from biology, not directly measured.
  • Limited sample size for HRD-Del subtype (n=6 patients).
  • Study restricted to treatment-naive patients; post-treatment immune remodelling is not captured.
  • Ascites immunophenotypes are shown to be unrepresentative of solid tumour TMEs, questioning the common use of ascites as a surrogate for tumour biology.
  • The mechanistic link between mutational processes and JAK-STAT/TGFbeta pathway activation remains correlative; causal experiments are not included.
  • How the findings translate to therapeutic strategies (e.g., combination of PARP inhibitors with immunotherapy in HRD tumours, or TGFbeta inhibitors in FBI tumours) requires prospective clinical testing.

Citations from this paper used in the wiki

  • “HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells.”
  • “Foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFbeta signalling and immune exclusion, with predominantly naive/stem-like and memory T cells.”
  • “Clonal 6p LOH was primarily observed in HRD-Dup cases, whereas subclonal distributions were more frequent in patients with FBI tumours.”
  • “Higher prevalence of 6p LOH in HRD-Dup was validated in an independent cohort (n = 1,298 patients) with available MSK-IMPACT sequencing (31% in BRCA1-mutant cases, 19% in BRCA2-mutant cases and 24% in CCNE1-amplified cases).”
  • “FBI tumours…are more resistant to chemotherapy and here are found to be immunologically inert.”

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