How early-stage colon cancer cells hide from the immune system

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"... A new study ... has identified one strategy that helps these precancerous cells avoid immune detection. The researchers found that early in colon cancer development, cells that turn on a gene called SOX17 can become essentially invisible to the immune system. ...

The researchers’ experiments revealed that when SOX17 is turned on in cancer cells, it helps the cells to create an immunosuppressive environment. Among its effects, SOX17 prevents cells from synthesizing the receptor that normally detects interferon gamma, a molecule that is one of the immune system’s primary weapons against cancer cells. 

Without those interferon gamma receptors, cancerous and precancerous cells can simply ignore messages from the immune system, which would normally direct them to undergo programmed cell death. ..."

"... A new study ... has found a signal that short circuits the alarm system in stem cells in the colon and enables the cells to evade the immune system and develop into cancers in animal models. The work, published in Nature, is the first to look deeply at molecular changes that protect cancer cells from surveillance by the immune system at the earliest stages of cancer development, when the cells are most vulnerable to immune detection. ...

SOX17 orchestrates a genetic program that is only supposed to be turned on during fetal stages of development. The fetus forms organs quietly, without stimulating immune attack, and SOX17 may be part of that process. 

But when SOX17 is turned on in an adult, it hampers the cell’s ability to sound alarms when things go wrong. The cells change from highly immune-susceptible LGR5+ cells to SOX17 cells that cloak from immune recognition. ... "

From the abstract:

"A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer; however, much less is known about how pre-malignant or early invasive tumours evade immune detection. Here, to understand this process in early colorectal cancers (CRCs), we investigated how naive colon cancer organoids that were engineered in vitro to harbour Apc-null, KrasG12D and Trp53-null (AKP) mutations adapted to the in vivo native colonic environment. Comprehensive transcriptomic and chromatin analyses revealed that the endoderm-specifying transcription factor SOX17 became strongly upregulated in vivo. Notably, whereas SOX17 loss did not affect AKP organoid propagation in vitro, its loss markedly reduced the ability of AKP tumours to persist in vivo. The small fraction of SOX17-null tumours that grew displayed notable interferon-γ (IFNγ)-producing effector-like CD8+ T cell infiltrates in contrast to the immune-suppressive microenvironment in wild-type counterparts. Mechanistically, in both endogenous Apc-null pre-malignant adenomas and transplanted organoid-derived AKP CRCs, SOX17 suppresses the ability of tumour cells to sense and respond to IFNγ, preventing anti-tumour T cell responses. Finally, SOX17 engages a fetal intestinal programme that drives differentiation away from LGR5+ tumour cells to produce immune-evasive LGR5− tumour cells with lower expression of major histocompatibility complex class I (MHC-I). We propose that SOX17 is a transcription factor that is engaged during the early steps of colon cancer to orchestrate an immune-evasive programme that permits CRC initiation and progression."

How early-stage cancer cells hide from the immune system | MIT News | Massachusetts Institute of Technology A new study finds precancerous colon cells turn on a gene called SOX17, which helps them evade detection and develop into more advanced tumors.

One Genetic Switch Undermines Immune System’s Efforts to Thwart Colon Cancer (Dana Faber Cancer Institute)

SOX17 enables immune evasion of early colorectal adenomas and cancers (no public access) 

In these intestinal tumor cells, the Sox17 protein is labeled red. MIT researchers have found that when tumor cells turn on the Sox17 gene, it helps them evade immune detection, in part by turning off the expression of a protein called Lgr-5, labeled in green.

On the left, T cells begin to infiltrate the tumor after two weeks, but as the tumor initiates its immunosuppressive SOX17 program, they stop infiltrating, allowing the tumor to grow. On the right, the immunosuppressive SOX17 program is knocked out. T cells infiltrate without interruption and shrink the tumor.