Immune System Targets for Colorectal Cancer Immunotherapies Identified in Whole-Exome Analyses

A high load of neonatigens indicates colorectal cancer (CRC) is more likely to be permeated with disease-fighting white blood cells; an influx of which often indicates an immune system attack on the cancer. This study will inform immunotherapeutic approaches to CRC.1

Researchers performed whole-exome sequencing on CRC tumor samples from 619 patients, the information was then merged with data from tests of the immune system response to the tumors and with patient clinical data, including length of survival.

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"We were looking for genetic features that predict how extensively a tumor is infiltrated by lymphocytes [certain white blood cells] and which types of lymphocytes are present," said Marios Giannakis, MD, PhD, medical oncologist and clinical investigator at the Dana-Farber Gastrointestinal Cancer Treatment Center, and researcher at the Broad Institute of MIT and Harvard in Boston, Massachusetts, and co-lead author of the study.

"We found that tumors with a high 'neoantigen load,' which carry large quantities of neoantigens, tended to be infiltrated by a large number of lymphocytes, including memory T cells, which provide protection against previously encountered infections and diseases. Patients whose tumors had high numbers of neoantigens also survived longer than those with lower neoantigen loads."

Neoantigens are deviant forms of protein antigens found on normal cells that attract an immune response when needed. Genetic mutations often cause cancer cells to produce abnormal proteins, some of which get lifted to the cell surface, where they serve as a red flag to the immune system that something is amiss.

"There can be hundreds or thousands of neoantigens on tumor cells," Giannakis explained. "Only a few of these may actually provoke T cells to infiltrate a tumor. But the more neoantigens on display, the greater the chance that some of them will spark an immune system response."

Recent approaches for several types of cancer used immune checkpoint inhibitors to remove some of the barriers to an immune system attack on cancer. These therapies can be astonishingly effective but generally only work in patients whose immune systems have already launched an immune response to cancer. This study may help investigators identify which patients are most likely to benefit in new clinical trials of immune checkpoint inhibitors.

The study's genomic analysis of colorectal tumor samples also found several often-mutated genes that had not previously been strongly associated with the disease, including BCL9L, RBM10, CTCF, and KLF5. The discovery of their prevalence in colorectal cancer suggests that they may be valuable targets for new therapies.

"Our study helps shed light on the overall development of colorectal cancer," Giannakis remarked. "It also shows the insights that can be gained by integrating molecular research with findings from other areas such as epidemiology and immunology."

REFERENCE

1. Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma [published online ahead of print April 14, 2016]. Cell Reports. doi:10.1016/j.celrep.2016.03.075.

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