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Team Ties Tumor Microenvironment to Metastasis in Colorectal Cancer

NEW YORK (GenomeWeb) – Immune features in the colorectal cancer microenvironment may help in predicting risk of metastasis, according to a study appearing online today in Science Translational Medicine.

Researchers from France, the UK, Austria, and Germany considered mutations, amplifications, deletions, and gene expression patterns in primary tumors from more than 800 colorectal cancer patients with or without metastasis. Though they did not see genetic mutations or alterations with clear ties to metastasis, they did find that metastasis tended to be marked by declining cytotoxic immune gene expression and lower-than-usual lymphatic vessel representation — features related to the tumor's broader microenvironment.

"Strikingly, this comprehensive analysis revealed that the main parameters associated with dissemination to distant metastasis are immune-related and not tumor-related," senior author Jérôme Galon — an integrative cancer immunology researcher affiliated with INSERM, the University of Paris, and Sorbonne University — and his co-authors wrote. "It is striking to observe the major impact of the host adaptive immune response on all aspects of the metastatic process, including early metastatic invasion and synchronous and metachronous metastasis."

To look for tumor and microenvironment features that might impact metastasis, the researchers scrutinized new and existing genetic data on samples from 838 individuals with colorectal cancer in four research cohorts, including The Cancer Genome Atlas.

Sequence data for 48 potential driver genes was available already, but the team used the Ion AmpliSeq Cancer Hotspot Panel and Ion Torrent sequencing to assess 50 frequently mutated cancer genes in 214 of the other colorectal cancer tumors.

They did not see clear differences in the nature or frequency of gene mutations in primary tumors that metastasized and those that didn't. Likewise, microarray, RNA sequencing, and/or array comparative genomic hybridization experiments pointed to extensive overlap between expression and chromosome instability patterns in colorectal cancer samples with or without metastases.

Even so, primary tumors that metastasized appeared more prone to alterations or expression shifts involving immune-related genes or pathways.

That potential immune contribution was amplified when the team compared immune T cell and lymphatic vessel densities in tumors from individuals with or without metastases: lymphatic vessel density was significantly higher in primary tumors from individuals without metastasis, as was representation by T cells, cytotoxic T cells, and other immune cells.

Mutations in one gene — FBXW7 — did turn up more frequently in a subset of non-metastasizing primaries. And based on that gene's previously described role in dampening inflammatory immune activity, the researchers suspected these FBXW7 mutations might boost pro-inflammatory signaling.

The authors cautioned that the current analysis may have missed rare populations of metastasis-prone tumor cells, such as cancer stem cells. Still, their results suggested metastatic risk information can be gleaned from immune traits in the microenvironment, including cytotoxic T cell density patterns that can be picked up using an existing stratification tool called Immunoscore.

And based on their findings so far, Galon and his colleagues argued that there may be a benefit to treating colorectal cancer patients with compounds that boost cytotoxic T cell activity.

"[O]ur study supports the use of T cell-based immunotherapy at early-stage disease to prevent dissemination of tumor cells to develop distant metastasis," they wrote, "and also suggests that Immunoscore and the immune analysis of the primary tumor may help predict the presence and development of metastasis."