Achilles Heel of Immunotherapy-Resistant Cancers Revealed – and Eliminated – in Early Studies

 

Just-published research in Cell outlines a way to make even immunotherapy-resistant cancers treatable. Further studies are required, but the finding suggests an approach that would enable vast numbers of patients to benefit from immunotherapy who currently cannot.

Basically, researchers used an antibody that blocks TREM2 protein to empower immune cells to destroy tumors. When combined with an anti-PD-1 immunotherapy, the tumors were completely eliminated in mouse models.

Currently, only about a quarter of cancer patients respond to immunotherapy, because the tumors are highly adept at evading the immune system’s assault.

“Essentially, we have found a new tool to enhance tumor immunotherapy,” senior author Marco Colonna, M.D., professor of pathology at Washington University in St. Louis, said in a statement.

The potential therapy hinges upon blocking the TRIM2 protein. Dr. Colonna was familiar with TRIM2 through his work with Alzheimer’s disease. In that context, “TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer’s disease,” he explained in the August 11 paper in Cell. It is associated with underperforming immune cells – macrophages – in the brain.

Its value in cancer therapy is that TREN2 also is expressed by tumor-infiltrating macrophages, creating an immuno-suppressive microenvironment.

T cells have long been known for their ability to detect and destroy tumor cells, but tumors create an immune-suppressive environment around themselves that subdues T cells. Checkpoint inhibitors, a leading type of immunotherapy, awakens those T cells from their quiescence so they can attack the tumor. If the tumor environment is still immunosuppressive, however, checkpoint inhibition alone may not be enough to eliminate the tumor.

“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,” Colonna said. “So it’s actually an ideal target, because if you engage TREM2, you’ll have little effect on peripheral tissue.”

The logical hypothesis, reached by Dr. Colonna, and colleagues Martina Molgora, Ph.D., and Robert D. Schrieber, Ph.D., both of Washington University in St. Louis, and William Vermi, M.D., immunologist, University of Brescia, was that inhibiting TREM2 could reduce immunosuppression and enhance the tumor-killing powers of T cells.

They found that:

• TREM2 is expressed by tumor-associated macrophages in multiple tumor types.
• TREM2 deficiency and anti-TREM2 mAb treatment both curb tumor growth in mice.
• Anti-PD-1 treatment is more efficacious when TREM2 is either absent or engaged by a mAb.
• Modulating TREM2 remodels the tumor macrophage landscape.

In studies of sarcoma, tumor growth plateaued and, in a few cases, disappeared entirely among mice receiving either the TREM2 antibody or the checkpoint inhibitor. In all the mice that received both the TREM2 antibody and the checkpoint inhibitor, the tumors were completely rejected. Similar results were found when the studies were repeated using a colorectal cancer cell line. 

Analysis of the immune cells within the tumors showed that when the mice were treated with the TREM2 antibody alone, the suppressive macrophages were generally missing and that T cells were plentiful and active. Specifically, the researchers noted in the paper, “scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1 + and CX 3CR1 + macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses.” The conclusion, therefore, is that TREM2 antibodies have the potential to become a powerful way to enhance T cells’ anti-tumor activity.

In terms of moving forward, Dr. Colonna said, “The nice thing is that some anti-TREM2 antibodies are already in clinical trials for another disease. We have to do more work in animal models to verify these results, but if those work, we’d be able to move into clinical trials fairly easily because there are already a number of antibodies available.”

This research is being expanded to multiple cancer types, and the implications could be far-reaching. Macrophages containing TREM2 are expressed in multiple cancer types. Colonna said his team reported seeing TREM2 expressed in more than 200 cases of human cancers, and among multiple subtypes. Additionally, higher levels of TREM2 correlate with shorter survival among patients with either colorectal cancer or breast cancer, according to The Cancer Genome Atlas, a publicly available database of cancer genetics jointly maintained by the National Cancer Institute and the National Human Genome Research Institute.

The next step, Colonna said, is to perform animal testing using the human version of TREM2. “If that works, we’d be ready, I think, to go into a clinical trial.”

Complementary work was published in the same issue of Cell by researchers from the Weizmann Institute of Science in Israel, using a new single-cell RNA sequencing (scRNA-seq) technology called INs-seq that is designed for massively parallel recording of scRNA-seq and intracellular protein activity.

When corresponding author Ido Amit, Ph.D., and colleagues used INs-seq to map Arginase 1-expressing cells within tumor models, that research also revealed the immunosuppressive role of TREM2 in cancer. The work not only discovered novel Arg1 + Trem2 + regulatory myeloid (Mreg) cells, but also identified the markers, metabolic activity and pathways associated with these cells.

The Washington University of St. Louis and Weizmann researchers each found, in separate studies, that targeting TREM2 reduced tumor growth rates.

“Genetic ablation of TREM2 in mice inhibits accumulation of intra-tumoral Mreg cells, leading to a marked decrease in dysfunctional CD8 ⁺ T cells and reduced tumor growth,” the Weizmann researchers wrote.

These two papers are the latest in a stream of research correlating the presence of TREM2 in tumor cells with the progression of tumors. Although more research needs to be completed and advanced into the clinic, suppressing TREM2 appears to be a promising approach to treating even immunotherapy-resistant cancers.