Immunosuppressive niche engineering at the onset of human colorectal cancer.
Chandler D GatenbeeAnn-Marie C BakerRyan O SchenckMaximilian A R StroblJeffrey WestMargarida P NevesSara Yakub HasanEszter LakatosPierre MartinezWilliam C H CrossMarnix JansenManuel RodriguezChristopher J WhelanAndrea SottorivaSimon LeedhamMark Robertson-TessiTrevor A GrahamAlexander A R A AndersonPublished in: Nature communications (2022)
The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune "cold" ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC.
Keyphrases
- induced apoptosis
- early stage
- cell cycle arrest
- immune response
- squamous cell carcinoma
- endothelial cells
- climate change
- genome wide
- cell proliferation
- signaling pathway
- risk assessment
- radiation therapy
- gene expression
- toll like receptor
- machine learning
- human health
- case report
- induced pluripotent stem cells
- deep learning
- inflammatory response
- sentinel lymph node
- squamous cell