Abstract 3867: STAT1-related antigen processing and presentation dictates prognosis in the fibroblast-rich subtype of stage II/III colon cancer

Background: Molecular subtyping of colon cancer (CC) has repeatedly identified a poor-prognostic group of patients, characterized by high levels of stroma (particularly fibroblast) in the tumor microenvironment. To date, the benefit of standard 5FU-based adjuvant chemotherapy in these high-fibroblast (HiFi) patients has been unclear. Given TGF-β signaling is associated with HiFi tumors, a number of recent clinical trials have focussed on targeting TGF-β in these patients. While these efforts are ongoing, we set out to identify novel therapeutically-relevant biological signaling within HiFi tumors. Methods: Untreated stage II (n=215) and stage II/III (n=258) tumors were assigned a fibroblast score, using single-sample gene set enrichment analysis, enabling stratification into HiFi and LoFi groups based on their histology and transcriptome. Supervised stratification, based on relapse-free survival, within the HiFi group allowed for in silico discovery, interrogation and independent validation of the HiFi-specific biology underpinning relapse. Upstream regulators of these processes were identified as potential therapeutic targets, and assessed in an in vitro co-culture model, to confirm mechanistic signaling, and an in vivo HiFi model, to confirm efficacy. Results: We confirmed the poor prognosis of the HiFi group (p = 0.008), followed by discovery and independent validation of the prognostic value of STAT1-related signaling in stratifying HiFi tumors based on disease relapse (HR 0.2 (0.1-0.5) and 0.09 (0.02-0.47)). This signaling was significantly associated with activation of antigen processing and presentation in specific immune lineages (p < 0.001). In line with the upstream regulator analysis, treatment with poly I:C (a TLR3 agonist) increased STAT1-related signaling and antigen processing in an in vitro macrophage-stromal co-culture system. Conclusions: We have found that increased levels of STAT1-related signaling, resulting in antigen processing and presentation in specific subclasses of immune cells, is associated with reduced risk of recurrence in the otherwise poor-prognostic HiFi subtype of CC. Using in silico and in vitro methods, we demonstrate that poly I:C is a potential therapeutic option for patients with stromal-rich tumors. Results from ongoing in vivo validation in a HiFi mouse model will provide preclinical evidence of the utility of poly I:C in this setting and support a phase II clinical trial. Citation Format: Amy M. McCorry, Niamh A.