3D image illustrating immune cells attacking cancer cells in immunotherapy such as that used in cancers with mismatch repair deficiency
Credit: La Jolla Institute for Immunology

Salk scientists have found the immunotherapy treatment anti-CTLA-4 leads to considerably greater survival of mice with mesenchymal glioblastoma. Furthermore, they discovered that this therapy relied on CD4+ T cells infiltrating the brain and triggering the tumor-destructive activities of immune cells called microglia, which permanently reside in the brain. Published in Immunity, the findings suggest a possible new route of using immunotherapy for treating glioblastoma.

The limited efficacy of immunotherapies against glioblastoma prompted the Salk team to focus on a somewhat overlooked approach involving anti-CTLA-4 immunotherapy, CD4+ T cells, and microglia.

“We just know very little about how T cells function and infiltrate the brain, so we wanted to see how they get primed and activated in the glioblastoma setting since the treatment options are so lacking,” explains senior author Susan Kaech. “It rises right to the top where you would want a surgical scalpel—like a T cell—to help get rid of the tumor that avoids the blunt treatments we have now.”

Anti-CTLA-4 immunotherapy works by blocking cells from making the CTLA-4 protein, which, if not blocked, inhibits T-cell activity. It was the first immunotherapy drug designed to stimulate the immune system to fight cancer, but it was quickly followed by another, anti-PD-1, that was less toxic and became more widely used. Unfortunately, anti-PD-1 was found to be ineffective in multiple clinical trials for glioblastoma—a failure that inspired Kaech to see whether anti-CTLA-4 would be any different.

As for the specialized immune cells, CD4+ T cells are often overlooked in cancer research in favor of a similar immune cell, the CD8+ T cell, because CD8+ T cells are known to directly kill cancer cells. Microglia live in the brain full time, where they patrol for invaders and respond to damage—whether they play any role in tumor death was not clear.

First, the team used a mouse model that generates tumors containing mesenchymal-like stem cells. They administered either anti-PD-1 or anti-CTLA-4 monoclonal antibodies every three days for three weeks. As seen in human clinical trials, the anti-PD-1 therapy had no effect on median survival in these tumors; however, the ant-CTLA-4 treatment significantly extended survival by two- to three-fold and reduced tumor mutation burden. These results suggested that mesenchymal glioblastoma may be resistant to anti-PD-1 therapy and more intrinsically responsive to anti-CTLA-4.

Next, the team sought to figure out the mechanism why the anti-CTLA-4 therapy was more effective.

“We discovered that when mice were treated with anti-CTLA-4 antibodies, it prompted the CD4+ T cells to secrete interferon gamma which activates microglia to become more phagocytic and eat the tumor cells,” explains co-first author Dan Chen, a postdoctoral researcher in the Kaech lab. In the process, microglia retain bits of the tumor on their surfaces further stimulating the CD4+ T cells to produce more interferon gamma. This induces a long-lasting cycle between CD4+ T cells and microglia to continually devour more cancer cells.

“The CD4+ T cells are really the trigger here; we don’t yet know exactly why anti-CTLA-4 treatment leads to this release of CD4+ T cell response against the tumor,” says Kaech. “But, regardless of how, we can see this is having a pretty profound effect.” The CD4+ T cells are being unleashed and allowed to develop an anti-tumor response that is stronger in the face of anti-CTLA4 therapy. And these activities are affecting the local microglia that are not only inducing their tumoricidal states, but also leading to the ability of microglia to become tumor antigen-presenting cells that now continue to stimulate the CD4+ T cells.

“I have felt like T cells are going to be the true magic bullet that we need for this deadly disease, so discovering this pathway gives us a lot of hope,” adds Kaech. “Developing a partnership between CD4+ T cells and microglia is creating a new type of productive immune response that we have not previously known about.”

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