TREM-1 IN LUNG CANCER

CHICAGO — Triggering receptors expressed on myeloid cells (TREM-1) could be an important biomarker for lung cancer progression.

"I am really excited about this research, but it is nowhere near therapeutic," explained Hiren Mehta, MD, assistant professor of medicine at University of Florida Health in Gainesville.

He presented the research here at CHEST 2013: American College of Chest Physicians Annual Meeting, where it was a semifinalist for the Young Investigator Award. He called the work "hypothesis generating."

He began his presentation by describing lung cancer as one of the deadliest cancers worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers.

With continued lethality of NSCLC, "is there something that we are missing?" Dr. Mehta wondered. He turned his attention to the interaction between inflammation and cancer, and focused on TREM-1.

TREM proteins belong to the immunoglobulin superfamily of cell-surface receptors. TREM-1 is expressed on a select group of macrophages and neutrophils. Investigators have yet to identify the ligand for TREM-1; however, toll-like receptor ligands are known to induce the expression of TREM-1.

TREM-1 amplifies the inflammatory response. "We know from infection research that lipopolysaccharide activates this protein," Dr. Mehta explained. Blockade of TREM-1 improves survival in animal models of sepsis.

Previous work by Dr. Mehta and colleagues has shown that TREM-1 exacerbates inflammatory responses by inhibiting apoptosis of macrophages (Exp Cell Res. 2010;316:3140-3149). They reported that prostaglandins inhibit TREM-1 in a manner that is independent of the prostaglandin receptor and PPARɣ receptor.

In that publication, the researchers suggested that prostaglandins exhibit anti-inflammatory effects in a novel way, through the downregulation of TREM-1. Should TREM-1 expression prove important in the progression of NSCLC, therapeutic options, in the form of prostaglandins, would be readily available to decrease its expression and, perhaps, decrease mortality from NSCLC.

Scientists have begun to explore the role of TREM-1 in cancer, and the results are intriguing. TREM-1 is expressed in Kupffer cells in liver cancer. Some breast cancer cells also express TREM-1.

TREM-1 appears to accentuate inflammation in patients with cancer. Scientists suspect that TREM-1 works in the tumor microenvironment to facilitate cancer cell invasion and metastasis.

In their new research, Dr. Mehta and colleagues hypothesized that TREM-1 expression in tumor-associated macrophages regulates lung cancer progression. As a first step in addressing the hypothesis, they compared the expression of TREM-1 in human NSCLC specimens and in normal lung specimens.

With immunostaining and confocal microscopy, the researchers found that TREM-1 is highly expressed in specimens from patients with NSCLC. Dr. Mehta reported being intrigued that TREM-1 was not expressed on cancer cells, but rather on cells in the stroma.

TREM-1 expression colocalized with CD68 expression, confirming that tumor-associated macrophages express TREM-1. TREM-1 was not detected in macrophages from normal lung tissue.

Tumor tissue also showed expression in TREM-1 messenger RNA, relative to control tissue.

"At some point, TREM-1 could be a novel therapeutic target for NSCLC," explained session moderator Cristina A. Reichner, MD, FCCP, from Georgetown University in Washington, DC.

"There is potential in understanding downstream effects," she to Medscape Medical News.

Dr. Mehta expressed interest in further defining the mechanisms of induction of TREM-1 and examining its expression in the peripheral blood of patients with NSCLC.

Dr. Mehta and Dr. Reichner have disclosed no relevant financial relationships.

CHEST 2013: American College of Chest Physicians Annual Meeting. Presented October 27, 2013.