April 23, 2024

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Early Cancer Immune Evasion Accomplice Identified – SOX17

Early Cancer Immune Evasion Accomplice Identified – SOX17



Early Cancer Immune Evasion Accomplice Identified – SOX17

One of the primary roles of the human immune system is to monitor, detect, and kill cells harboring oncogenic mutations. Immune evasion is a hallmark of cancer, primarily studied in advanced or metastatic cancers. However, little is known about how malignant precursors or early invasive tumors evade immune surveillance and progress to advanced stages.

Recently, researchers from the Massachusetts Institute of Technology and Dana-Farber Cancer Institute published a study titled “SOX17 enables immune evasion of early colorectal adenomas and cancers” in the journal Nature.

The study, using organoid models of colorectal cancer (CRC), found that the transcription factor SOX17 is highly expressed in the early stages of CRC formation, protecting precancerous cells from immune attacks and aiding in the development and progression of colorectal cancer. Thus, inhibiting SOX17 or its activation pathway could offer a new approach for early-stage CRC treatment.

Early Cancer Immune Evasion Accomplice Identified - SOX17


Immune Evasion

Colorectal cancer usually originates from long-lived cells called intestinal stem cells, which continuously regenerate the lining of the intestine. Over their long lifespan, these cells may accumulate oncogenic mutations, leading to the formation of polyps, a precancerous growth that can eventually develop into metastatic colorectal cancer.

To further understand how these precancerous growths evade the immune system, the research team used their previously developed organoid technology—miniature colon tumors grown in a dish, which were then implanted into mice. In this case, the researchers engineered the tumors to express mutated versions of the cancer-related genes Kras, p53, and Apc (KrasG12D, p53 loss, Apc loss), commonly found in human colorectal cancer.

Once these tumor organoids were implanted into mice, the researchers observed a significant increase in SOX17 expression in the tumors. This gene encodes a transcription factor typically active only during embryonic development, helping to control intestinal development and vascular formation. The researchers further revealed that when activated in cancer cells, SOX17 helps create an immunosuppressive microenvironment. One of SOX17’s actions is to prevent cells from synthesizing the receptor for interferon gamma (IFNγ), one of the immune system’s main weapons against cancer cells. Without these IFNγ receptors, cancerous and precancerous cells can simply ignore signals from the immune system, avoiding programmed cell death.

The research team stated that one of SOX17’s main roles is to shut down the IFNγ signaling pathway in colorectal cancer cells and precancerous cells. By shutting down the IFNγ receptor signal in tumor cells, they can escape T cells and continue to grow in the presence of the immune system.

In addition to shutting down the IFNγ signal, cancer cells also reduce the production of major histocompatibility complex (MHC) proteins, which are responsible for presenting cancer antigens to the immune system. The insensitivity of these cancer cells to IFNγ also prevents them from producing chemokines, immune molecules that typically recruit T cells to help destroy cancer cells.

Targeting SOX17

When the research team implanted colon tumor organoids with knocked-out SOX17 genes into mice, their immune systems were able to more effectively attack these tumors, essentially eliminating the tumors’ ability to survive. This suggests that targeting and inhibiting SOX17 could offer a new approach for early-stage colorectal cancer treatment.

Furthermore, the research team analyzed gene expression data from human colorectal cancer patients, which showed that SOX17 is often highly expressed in early-stage colorectal cancer but decreases as the tumor becomes more invasive and metastatic.

The research team stated that these findings are significant because as colorectal cancer becomes more invasive and metastatic, other mechanisms create an immunosuppressive environment, reducing the importance of SOX17.

As a transcription factor, SOX17 is considered a challenging drug target, partly due to its structurally complex nature. Therefore, the research team plans to identify other proteins that interact with SOX17, aiming to find easier ways to block its interaction. Additionally, they plan to further explore what triggers the activation and high expression of SOX17 in precancerous cells.

Paper link

Early Cancer Immune Evasion Accomplice Identified – SOX17


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