How a protein implicated in Alzheimer's could enhance cancer immunotherapy

Variants of TREM2, a receptor expressed by immune cells, have been linked to the development of Alzheimer’s disease. Now scientists have shed light on a potential new use for the protein in cancer treatment.

TREM2 is also found in tumor-infiltrating myeloid cells, which sometimes create an immunosuppressive environment that helps tumors escape immune surveillance. In a study published in Cell, a team at Washington University School of Medicine in St. Louis showed that targeting the protein could be a potential new way to enhance the power of immuno-oncology drugs.

In tumor-bearing mice, treatment with an anti-TREM2 monoclonal antibody, combined with a PD-1 inhibitor, worked better at controlling tumor growth than either drug did alone, the team found.

To understand the role of TREM2 in anti-tumor immune responses, the researchers removed the gene that encodes the protein in mice and injected them with cancer cells. Compared with wild-type mice, these TREM2-lacking animals showed consistently reduced tumor progression.

Moreover, significantly more CD8+ and CD4+ T cells—which are critical to mounting an immune response against cancer—appeared to have been activated in TREM2-negative mice. This led the researchers to hypothesize that inhibiting TREM2 could improve responsiveness to anti-PD-1 blockade, which works by removing the “brakes” that tumors use to subdue immune cells.

First, the scientists used a suboptimal schedule for anti-PD-1 administration, starting treatment well after the injection of cancer cells. As a result, only 40% of the control mice rejected the tumor, whereas all of those without TREM2 did.

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They then tested the effect of therapeutic modulation of TREM2 with a mouse-specific antibody. In a mouse model of sarcoma, the TREM2 antibody or PD-1 inhibitor alone produced slower tumor growth compared to placebo. But the combination of anti-TREM2 and anti-PD-1 treatments led to complete tumor control in all mice tested, the team reported.

TREM2 has become a prime target in many disease areas because of its expression in immune cells. For example, in Alzheimer’s, TREM2 is believed to affect the brain's ability to clear out toxic beta-amyloid and tau proteins that have been implicated in the disease. Previous Fierce 15 winner Alector, in collaboration with AbbVie, is working on a TREM2-activating antibody, dubbed AL002, to treat the neurological disorder.

Another team led by the University of Michigan previously found that some macrophages in the liver had high expression of TREM2, which was associated with the severity of nonalcoholic steatohepatitis (NASH).

By exploring The Cancer Genome Atlas database, the Washington University researchers found that increased TREM2 expression was correlated poorer patient outcomes in colorectal cancer and triple-negative breast cancer.

They believe the findings suggest anti-TREM2 could be a new avenue for boosting checkpoint inhibitors. “When we looked at where TREM2 is found in the body, we found that it is expressed at high levels inside the tumor and not outside of the tumor,” Marco Colonna, the study’s senior author, said in a statement. “So it's actually an ideal target, because if you engage TREM2, you'll have little effect on peripheral tissue.”

Next up, the team is expanding its study of TREM2 to other types of cancers and to a humanized mouse model using human antibodies.