A recently published study has shed light on the role of SOX17 in aiding immune evasion in colorectal adenomas and cancers. While the phenomenon of immune evasion is a hallmark of cancer, it has mostly been studied in the context of locally advanced and metastatic cancer. However, not much is known about how pre-malignant and invasive tumors are able to evade detection by the immune system.
To address this gap in understanding, researchers investigated colon cancer using naive colon cancer organoids that were genetically engineered to harbor Apc-null, KrasG12D Trp53-null (AKP) mutations and then adapted to the native colonic environment in vivo. Through comprehensive transcriptomic and chromatin analyses, the research team found that the endoderm-specifying transcription factor SOX17 was strongly upregulated in these organoids when they were in vivo.
Interestingly, when SOX17 was knocked out, it had a significant impact on the ability of AKP tumors to persist in vivo, even though it did not affect their propagation in vitro. The researchers noted that only a small fraction of SOX17-null tumors were able to grow, and these tumors showed a higher presence of interferon-? (IFN?)-producing effector-like CD8+ T cells compared to the immune-suppressive microenvironment found in the wild-type tumors.
In terms of mechanism, the study found that SOX17 suppresses the ability of tumor cells to sense and respond to IFN?, thereby preventing anti-tumor T cell responses. Additionally, SOX17 was shown to drive the differentiation of tumor cells away from LGR5+ cells towards immune-evasive LGR5- cells with lower expression of major histocompatibility complex class I (MHC-I) molecules.
Based on their findings, the researchers propose that SOX17 is a crucial transcription factor involved in orchestrating an immune-evasive program during the initiation and progression of colorectal cancer. By engaging in a fetal intestinal program, SOX17 plays a key role in driving the differentiation of tumor cells towards a state that is less susceptible to detection and attack by the immune system.
This study not only sheds light on the immune evasion mechanisms at play in colorectal cancer but also highlights the potential of SOX17 as a therapeutic target for improving immunotherapy outcomes in this type of cancer. The findings may pave the way for developing novel strategies to enhance immune responses against colorectal cancer and improve patient outcomes.
