bioGenous Science Focus

In this study, the authors comprehensively analyzed epigenetic and transcriptomic changes during colorectal cancer progression using an in vivo organoid transplantation model, identifying SOX17 as a key factor promoting tumor immune evasion. In colorectal cancer organoids, the transcription factor SOX17 is induced, promoting tumor cell differentiation into a phenotype that evades immune recognition. This process suppresses tumor cells' responsiveness to IFN-γ, reduces the infiltration of effector CD8+ T cells, and consequently establishes an immunosuppressive tumor microenvironment. This mechanism drives the formation and progression of early-stage colorectal tumors.

Immunotherapy has become a primary approach in cancer treatment. However, many tumors can evade immunotherapy, and we know very little about how pre-cancerous or early-stage tumors escape immune detection. Colorectal cancer (CRC) is a typical example of evading immunotherapy, which studies have found is due to its highly immunosuppressive tumor microenvironment (TME). In advanced cancer stages, since the immunosuppressive TME is already established, identifying the mechanisms that orchestrate this immune dysfunction in early cancer stages is crucial for improving current immunotherapies.

Recently, the research group led by Ömer H. Yilmaz collaborated with Judith Agudo's group to publish a research paper titled “SOX17 enables immune evasion of early colorectal adenomas and cancers” in Nature. In this study, the authors comprehensively analyzed epigenetic and transcriptomic changes during colorectal cancer progression using an in vivo transplantation model of colorectal cancer organoids. They identified a key factor, SOX17, that promotes tumor immune evasion. In colorectal cancer organoids, the transcription factor SOX17 is induced, promoting tumor cell differentiation into a phenotype that evades immune recognition. This process suppresses tumor cells' responsiveness to IFN-γ, reduces the infiltration of effector CD8+ T cells, and consequently establishes an immunosuppressive tumor microenvironment. This mechanism drives the formation and progression of early-stage colorectal tumors.

First, the authors transplanted colorectal cancer organoids into mouse colons to simulate the progression of colorectal cancer from early to advanced stages in vivo. This enabled analysis of transcriptional and epigenetic changes during cancer evolution. The results revealed that the colonic environment in mice induces stable, heritable transcriptional and epigenetic alterations in colorectal cancer organoids. Concurrently, a significant upregulation of the SOX17 transcription factor was observed. Consequently, the authors concluded that transplanting colorectal cancer organoids into the colonic environment of mice leads to upregulation of the SOX17 transcription factor.

Next, the authors investigated the role of the SOX17 transcription factor in colorectal cancer progression. Using CRISPR-Cas9 technology, they generated SOX17 knockout colorectal cancer organoids and transplanted them into mice. Results showed that only 6% of transplanted mice developed tumors in the absence of SOX17, with significantly smaller tumor volumes compared to the control group. Furthermore, SOX17 deficiency induced enhanced immune infiltration in tumors, severely inhibiting their growth. In contrast, mice transplanted with normal colorectal cancer organoids exhibited the opposite immune infiltration phenotype. In immunodeficient mice, however, knocking out SOX17 had no effect on tumor growth. Combining these three sets of results, the authors conclude that the SOX17 transcription factor promotes tumor progression in vivo by inhibiting immune infiltration.

The authors conducted deeper investigations into how the SOX17 transcription factor regulates the tumor-associated immune microenvironment within tumors. Effector CD8+ T cells, possessing potent tumor-killing capabilities, constitute the primary immune cell population targeting tumor cells. T cell tracking revealed that exhausted CD8+ T cells dominated in the control group by week 4, whereas the proportion of exhausted CD8+ T cells was significantly reduced in the SOX17 knockout group. Further studies revealed that T-cell infiltration markedly decreased after week 4 in the control group, whereas SOX17 knockout enhanced T-cell infiltration and significantly increased the ability of T cells to produce IFN-γ and TNF. Analysis indicated that the IFN-γ induction pathway was one of the most highly upregulated pathways in SOX17-knockout organoid tissues. Thus, the authors concluded that SOX17, induced as a transcription factor during tumor progression in vivo, suppresses IFN-γ signaling pathway gene expression in cancer cells. This inhibits activated effector CD8+ T cells from recognizing tumor cells, effectively preventing the formation of an anti-tumor T-cell immune microenvironment and protecting colorectal cancer from clearance.

Subsequent analysis of SOX17 function in colonic adenomas revealed consistent activity with that observed in colorectal cancer organoids. This indicates SOX17 plays a critical role not only in shaping the tumor immune microenvironment during early colorectal cancer development but also in mediating immune evasion responses in colonic adenomas. Furthermore, the authors observed that SOX17 exhibits strong expression in both colonic adenomas and early-stage colorectal cancer. Its expression levels inversely correlate with CD8+ T cell infiltration, thereby promoting immune evasion in both colonic adenomas and colorectal cancer.

Through the above studies, the authors revealed that the SOX17 transcription factor promotes LGR5-stem cell differentiation by reprogramming tumor cell epigenetics. It inhibits tumor cells' perception and response to IFN-γ, thereby preventing anti-tumor T cells from immunologically clearing tumor cells. This creates an early tumor-suppressive microenvironment particularly conducive to colorectal cancer formation, enabling its smooth development and rapid progression. In summary, SOX17 enables cancer progression by suppressing IFN-γ perception and promoting adaptive immune evasion.