A 4-chemokine signature to predict intermediate immunogenicity in homologous recombination repair deficient tumors.

Abstract

2546 Background: Treatment responses to immune checkpoint blockade (ICB) associate with T cell tumor inflammation. Tumors with mismatch repair deficiency display an inflammatory tumor phenotype and respond to ICB. Similarly, tumors with homologous recombination repair deficiency (HR-d) may be primed for ICB treatment. We have previously shown that a panel of 4 chemokines identifies a subclass of pancreatic cancer with markers of T cell-inflammation. Here, we evaluated this 4-chemokine signature in cancer types with HR-d molecular subclasses. Methods: We combined paired transcriptomes and genomic data of breast (n = 699), ovarian (n = 174) and prostate (n = 457) cancers from the Cancer Genome Atlas and tumor-enriched pancreas cancers (n = 121) to evaluate the 4-chemokine signature in HR-d vs. HR-proficient tumors across these 4 cancers. Metrics of antitumor immunity were also compared. Results: Across tumor types, elevated expression of the 4-chemokine signature (chemokine-hi) associated with transcriptional hallmarks of a T cell-mediated antitumor response, including antigen presenting cell stimulation, antigen presentation, and T cell activity. In tumors with a predominant COSMIC signature 3, which associates with HR-d, the 4-chemokine signature predicted intermediate levels of T cell-inflammation. Conclusions: These data suggest that 1) the 4-chemokine signature may be a clinically relevant biomarker in identifying subclasses of tumours responsive to immunotherapies, and that 2) HR-d tumors harbor intermediate immunogenicity. Correlation of treatment responses to immunotherapies with the 4-chemokine signature is needed validate its predictive value as a biomarker for treatment stratification with immunotherapies.[Table: see text]