Multiomic analysis of colorectal adenocarcinoma reveals a new subtype of myofibroblastic cancer-associated fibroblasts that express high levels of B7-H3 and have poor-prognosis value.

BACKGROUND: The high mortality rate of patients with colorectal cancer combined with the lack of nontoxic and efficient personalized treatments makes it urgent to develop new targeted therapies for this disease. B7-H3 appears to be a good target, as it is overexpressed in tumor tissue compared with normal tissue. However, B7-H3 is a molecule with ambivalent functions and is expressed by different cell types. This complexity has contributed to the delay in identifying cell subtypes that express B7-H3 and their potential role in colorectal oncogenesis. METHODS: In this integrated multiomics study, we used in silico bulk, single-cell, and spatial transcriptomic data to investigate the clinical and biological characteristics of tumors with high B7-H3 expression, the specific cell types expressing high levels of B7-H3, and their temporal appearance during colorectal oncogenesis. RESULTS: We found that tumors with high B7-H3 expression corresponded to tumors with a predominant stroma composed mainly of fibroblasts. Among them, two subtypes of extracellular matrix-related myofibroblastic cancer-associated fibroblasts and profibrotic pericytes specifically expressed high levels of B7-H3, the former being an independent factor for poor prognosis in patients with colorectal cancer. Finally, by examining precancerous lesions, we report that fibroblast subtypes with high levels of B7-H3 appear early during oncogenesis, especially at the inflamed stage. CONCLUSIONS: We suggest that anti-B7-H3 immunotherapies might preferentially target cells from the microenvironment rather than tumor cells. This is particularly important for understanding the mode of action of the anti-B7-H3 antibody‒drug conjugate, which is currently being tested in clinical trials in several solid tumors.