Genomics Makeup of Colorectal Tumors Predicts Immune Response

A study based on whole-exome sequencing and immune response finds that colorectal cancers (CRCs) heavily bedecked with tumor-related neoantigens are likely to be permeated with disease-fighting white blood cells (WBCs). The discovery helps sharpen research into therapies that make tumors more vulnerable to such an attack and into companion diagnostics.

A multi-institute team led by researchers at Dana-Farber Cancer Institute (Boston, MA, USA) and Broad Institute of MIT & Harvard (Cambridge, MA, USA) made the discovery by combining several data sets from patients in 2 large health-tracking studies, the Nurses' Health Study and the Health Professionals Follow-up Study. First the team performed whole-exome sequencing on CRC tumor samples from 619 patients, then merged this information with data from tests of the immune system's response to the tumors and with patient clinical data, including length of survival.

"We were looking for genetic features that predict how extensively a tumor is infiltrated by lymphocytes and which types of lymphocytes are present," said co-lead author Marios Giannakis, MD, PhD, "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 normal cell protein antigens, generally due to genetic mutations. "There can be 100s or 1000s of neoantigens on tumor cells," Dr. 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."

Therapies based on immune checkpoint inhibitors work by removing some of the barriers to an immune system attack on cancer. Although these agents have produced astonishing results in some cases, they're generally effective only in patients whose immune system has already launched an immune response the cancer. By showing that tumors with high antigen loads are apt to be laced with T-cells – and therefore to have provoked an immune response – the study may lead to development of a companion diagnostic test and help identify which patients are most likely to benefit in new clinical trials of immune checkpoint inhibitors.

The study's genomic analysis of CRC 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 CRC suggests that they may be valuable targets for new CRC therapies.

"Our study helps shed light on the overall development of CRC," Dr. 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."

The study, by Giannakis M, Mu XJ, Shukla SA, et al, was published April 14, 2016 in the journal Cell Reports.

Related Links:
Dana-Farber Cancer Institute
Broad Institute of MIT & Harvard