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Immune Gene Study Uncovers Cytokine Alterations Associated with Colorectal Cancer Progression

NEW YORK (GenomeWeb News) – Copy number and expression shifts involving cytokine immune genes in colorectal cancer samples can offer insights into immune involvement in the disease and its propensity for progression, a new study suggests.

Members of a French-led international team assessed more than 100 colorectal cancers (CRCs), using array comparative genomic hybridization and array-based expression profiling to monitor gains, losses, and expression levels for dozens of genes encoding various cytokines and the proteins interacting with them. The work, published online today in Science Translational Medicine, pointed to 13 cytokine genes with levels that can vary in CRC tumors.

In patients with metastatic CRC, the team identified recurrent deletions affecting a small set of cytokines, for instance. Of those, a single chromosome 4 cytokine called IL15 was both deleted and showed lower-than-usual expression patterns in patients with metastatic CRC.

Follow-up experiments indicated that losses of IL15 are likely linked to diminished proliferation of B and T lymphocytes around the tumor, perhaps contributing to the poorer survival outcomes observed in individuals with the IL15 deletions.

"These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15," wrote the authors, led by corresponding author Jérôme Galon, a researcher affiliated with INSERM, Paris Descartes University, and the Pierre and Marie Curie University.

"Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor," they added, "and the importance of local active lymphocyte proliferation for patient survival."

Prior studies indicate that adaptive immune cell responses in and around CRCs influence survival in those with the disease, the researchers noted, and individuals with especially strong immune responses have been found to survive much longer than those with low or intermediate local immune reactions.

Nevertheless, the complex suite of immune and tumor interactions that can affect CRC patient outcomes remains poorly defined.

For their new study, researchers focused on a set of secreted and membrane-bound immune proteins known as cytokines, which help to lure white blood cells to sites of inflammation and cue other immune responses.

They reasoned that some of these genes might become altered during cancer progression — a possibility they explored using aCGH to profile chromosomal gains and losses affecting 59 cytokine protein-coding genes in 109 CRCs.

In addition, the team considered expression of these cytokines with quantitative real-time PCR.

Indeed, the analysis uncovered a dozen chromosome gains or losses already linked to CRC. Among individuals with unusual cytokine copy numbers, the team saw expression shifts affecting 13 cytokine- and/or receptor-coding genes.

While many CRCs did not show altered cytokine copy number, the team noted that the presence of certain cytokine amplifications was associated with a lack of tumor metastasis to the lymph nodes or to other distant sites in the body.

On the other hand, CRC patients with metastases tended to have deletions affecting a handful of cytokines, including IL15, IL2, IL8, and IL21, researchers reported. Deletions involving three of the same cytokines were also associated with higher risk of relapse. Of those, one was prone to both deletion and diminished expression in CRC patients: IL15.

With the help of a program called CluePedia, the researchers brought together expression data, in silico information, and functional data for 105 CRCs to take a look at the immune network affected by changes to IL15.

Through that analysis, coupled with other available data on immune cells and follow-up experiments, the team determined that glitches in IL15 likely diminish the proliferation of lymphocytes known as T cells and B cells. That, in turn, appears to dampen immune responses in ways that negatively impact CRC patient survival.

Based on their findings, the study's authors argued that IL15 losses may serve as a marker for CRC progression or perhaps even make a feasible target for future CRC treatments. "Our findings represent major progress toward improving cancer patient prognosis using IL15 [as a] biomarker," they concluded, "and the potential of IL15 as [a] target for immunotherapeutic treatment of cancer."

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