TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory

The scientist Marta M. Alonso from Spain recently reported their finding on the potential of TIM-3 (HAVCR2) in targeting Diffuse Intrinsic Pontine Glioma (DIPG).

TIM-3 is highly expressed in DIPGs

In this study, researchers investigate the potential of targeting TIM-3, an immune checkpoint molecule, as a therapeutic strategy for Diffuse Intrinsic Pontine Glioma (DIPG), an aggressive brain stem tumor with a high mortality rate. Previous treatment options have offered only temporary relief and are not curative. However, the researchers found that inhibiting TIM-3 in syngeneic models of DIPG led to prolonged survival and produced long-term survivors free of disease with immune memory. This effect was attributed to the direct inhibition of TIM-3 in tumor cells, the coordinated action of different immune cell populations, and the secretion of chemokines/cytokines creating a proinflammatory tumor microenvironment that supports a potent antitumor immune response. These findings suggest that TIM-3 inhibition could be a potential therapeutic approach for DIPG, opening up new avenues for clinical trials.

TIM-3 expression in diffuse intrinsic pontine glioma (DIPG) was determined through an analysis of patient samples and in silico studies. The researchers used data from various databases to analyze the expression of TIM-3 in diffuse intrinsic pontine glioma (DIPG). The databases they utilized include PedcBioPortal, Kids First Data Resource Portal, and the St. Jude dataset. The researchers discovered that TIM-3 is highly expressed in the tumor microenvironment and tumor cells of DIPG patients. This finding was supported by the observation that TIM-3 co-expressed with the tumor cell marker nestin in an in vivo orthotopic murine DIPG model. Furthermore, the expression of TIM-3 was found to be higher in DIPG murine cell lines with the H3.3K27M mutation compared to those with the H3.1K27M mutation or without the mutation. These findings collectively demonstrate that TIM-3 is indeed highly expressed in DIPG.

TIM-3 is related with survival and tumorigenity

To investigate the role of TIM-3 in survival and tumorigenicity, researchers performed loss-of-function studies by knocking out or reducing TIM-3 expression in human and murine DIPG cell lines. They observed that TIM-3 knockout was lethal in all human DIPG cell lines evaluated, and inducible knockdown of TIM-3 significantly reduced the viability of these cells. Furthermore, the addition of an anti-TIM-3 human antibody also decreased the viability of the cell lines. They also obtained viable murine DIPG cell lines lacking TIM-3 expression, and these cells displayed reduced colony formation, metabolic activity, and migratory capacity compared to control cells.

To determine the importance of TIM-3 expression in tumorigenicity in vivo, the researchers implanted TIM-3 knockout cell lines into immunocompetent mice. They found that mice bearing TIM-3 knockout cells had significantly longer overall survival than those bearing control cells, with some mice surviving up to six times longer . These findings demonstrated the crucial role of TIM-3 in DIPG tumorigenesis in vivo .

Blocking TIM-3 induces an anti-glioma effect in immunocompetent DIPG models and results in immune memory

To investigate the effectiveness of blocking TIM-3, the researchers conducted experiments in syngeneic models of diffuse intrinsic pontine glioma (DIPG). They treated the tumor cells with a human anti-TIM-3 antibody and assessed the viability of the cells. The researchers also analyzed the tumor microenvironment and looked for changes in immune cell populations and the secretion of chemokines/cytokines. They examined the direct effect of TIM-3 inhibition in tumor cells and the coordinated action of various immune cell populations. Additionally, they evaluated the antitumor effect, survival rates, and generation of immune memory in the animals.

The findings of the study indicate that blocking TIM-3 in DIPG models prolongs survival and leads to long-term survivors free of disease. The blockade of TIM-3 produces a significant antitumor effect driven by the direct effect of inhibiting TIM-3 in tumor cells, the coordinated action of multiple immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. The researchers also observed the activation of T cells and the generation of immune memory, effectively preventing tumor recurrence.

Based on their findings, the researchers suggest that TIM-3 inhibition could be a potential therapeutic strategy for treating DIPG. These results open up new avenues for clinical trials and further investigation into the use of TIM-3 blockade as a potential treatment option for this aggressive brain stem tumor.

TIM-3 blockade efficacy is due to the coordinated interactions of several immune populations in the TME

The researchers believe that the efficacy of blocking TIM-3 is due to the coordinated interactions of several immune populations in the tumor microenvironment (TME) . They found that TIM-3 blockade resulted in increases in proinflammatory populations in the TME, including T cells, natural killer (NK) cells, and microglia.

To further understand the contributions of these immune populations to the therapeutic effect, the researchers conducted depletion experiments. They found that depletion of NK cells, CD4+ T cells, or CD8+ T cells led to a partial loss of the therapeutic effect. However, depletion of both NK and CD4+ T cells or NK and CD8+ T cells resulted in a significant decrease in the therapeutic effect, indicating that the combined action of these immune populations is necessary for the efficacy of TIM-3 blockade.

Furthermore, the researchers used immunodeficient mice lacking T, B, and NK cells but having macrophage and microglial populations to evaluate the roles of macrophages and microglia. They found that depletion of microglia/macrophages resulted in a total loss of the therapeutic effect, indicating the importance of these populations in producing a functional immune response.

Overall, these findings suggest that the efficacy of blocking TIM-3 in DIPG is due to the coordinated interactions of immune populations in the TME, including T cells, NK cells, macrophages, and microglia. This coordinated action leads to a proinflammatory tumor microenvironment that favors a potent antitumor immune response .