Scientists Discover That Inhibiting TREM2 Can Help Immunotherapy in Two Ways

Recently, the latest research results published by the research team of Washington University in St. Louis (WUSTL) in the journal Science Immunology showed that after knockout the important cancer-promoting receptor TREM2 on macrophages, the intestinal microenvironment will also change to an inflammatory state. Among them, Ruminococcus gnavus will proliferate significantly, promoting the proliferation and activation of CD4+T cells in the intestine, and migrating to the tumor site in large numbers, making PD-1 inhibitor treatment more effective.

Readers who are familiar with macrophage-related research will definitely not feel unfamiliar when seeing TREM2. It is considered a "big star" in the field in recent years, and the source is the heavyweight results published by the WUSTL team that conducted this study in "Cell" in 2020, which confirmed that TREM2 is a cancer-promoting receptor commonly expressed by tumor-associated macrophages (TAMs) in solid tumors. Inhibiting it can reshape TAMs and effectively sensitize immunotherapy.

But it is obvious that the scope of TREM2's influence is not limited to macrophages infiltrating into tumors. This time, WUSTL researchers wanted to see if they could find "immunotherapeutic probiotics" in the intestine that are affected by the knockout of TREM2. For this purpose, the researchers designed two special groups of mouse experiments, both of which compared the effects of knockout TREM2 on the immune response of mice. However, the first group of mice were raised together with the experimental group (TREM2-/-) and the control group (TREM2+/+), and the second group was raised separately.

The experimental results showed that without other external interventions such as immunotherapy, the tumor burden of the two groups of TREM2-/- mice was indeed slightly lower than that of the control group mice, which was consistent with the initial conjecture. However, when treated with PD-1 inhibitors, the experimental and control mice in the first group had similar treatment responses (the experimental group in the second group had a better response), which was not consistent with the setting that TREM2 was not knocked out in the control group. The researchers speculated that this might be due to the exchange of intestinal flora in mice due to co-feeding.

Next, the researchers confirmed through a special transplantation experiment that the significant changes in the intestinal flora of TREM2-/- mice occurred after treatment with PD-1 inhibitors, and that changes in intestinal flora were a necessary condition for mice to effectively suppress cancer. After multiple steps of experimental screening, the researchers determined that the significant enrichment of R. gnavus after treatment with PD-1 inhibitors was the reason why PD-1 inhibitors had a better anti-cancer effect on TREM2-/- mice (but only partially dependent).

Figure 1. Increased relative abundance of R. gnavus is specifically associated with TREM2 deficiency upon anti-PD-1 treatment. (Di Luccia B, et al., 2024)

While R. gnavus was enriched, PD-1 inhibitor treatment also caused "subclinical inflammation"-like changes in the intestines of TREM2-/- mice, and the expression of genes related to T cell activation, antigen presentation and immune cell migration was significantly enriched. Immune stimulation and inflammatory macrophage subsets in the intestine also slightly prevailed, and they may have responded to PD-1 inhibitor treatment. At the same time, the proportion of CD4+T cells that can produce tumor necrosis factor (TNF) in the intestine also increased significantly. The researchers also confirmed through fluorescent protein tracing that these CD4+T cells will migrate to the tumor-draining lymph nodes and join the anti-cancer battlefield.

Finally, the researchers decided to directly evaluate the effect of R. gnavus on the anti-tumor immune response. That is, after subcutaneous inoculation of cancer cells in mice, R. gnavus was enriched in the intestines of mice by oral gavage. Then, treatment with PD-1 inhibitors achieved a significant enhancement of the tumor shrinkage effect, and macrophages in the tumor also underwent positive remodeling that was beneficial to anti-cancer.

Two years ago, the WUSTL research team launched a clinical study of anti-TREM2 monoclonal antibodies combined with PD-1 inhibitors for patients with solid tumors. The discovery of the important role of intestinal flora in the absence of TREM2 has given the relevant clinical research another mission: to find more microorganisms that are beneficial to immunotherapy and try to use them as a new generation of "probiotic weapons" for sensitizing immunotherapy.

References

Di Luccia B, et al. TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy. Science immunology, 2024, 9(95): eadi5374.

Molgora M, et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell, 2020, 182(4): 886-900. e17.

Molgora M, et al. TREM2: A new player in the tumor microenvironment//Seminars in immunology. Academic Press, 2023, 67: 101739.