Immune checkpoint blockade (ICB) immunotherapy has shown little effectiveness against glioblastoma, but Salk Institute scientists have now shown that in mice models of glioblastoma anti-CTLA-4 immunotherapy does lead to improved survival. Their newly reported studies showed that the effectiveness of this form of therapy was dependent on CD4+ T cells infiltrating the brain and triggering the tumor-destructive activities of immune cells called microglia, which permanently reside in the brain. The researchers suggest that their findings could lead to more effective immunotherapies for treating brain cancer in humans

“There are currently no effective treatments for glioblastoma—a diagnosis today is basically a death sentence,” said Susan Kaech, PhD, director of the NOMIS Center for Immunobiology and Microbial Pathogenesis. “We’re extremely excited to find an immunotherapy regimen that uses the mouse’s own immune cells to fight the brain cancer and leads to considerable shrinkage, and in some cases elimination, of the tumor.”

Kaech is senior author of the team’s published paper in Immunity, titled, “CTLA-4 blockade induces an MHC-II+ microglia-Th1 cell partnership that stimulates microglial phagocytosis and anti-tumor function in glioblastoma.” In their paper, the researchers concluded, “Collectively, our data reveal that the partnership between microglia and CD4+ T cells is a key driver for glioblastoma control, particularly of mesenchymal subtypes, offering new therapeutic avenues for treating such a formidable disease.”

Glioblastoma is the most common and deadliest form of brain cancer, and there are no effective therapies, the authors noted. The tumor grows rapidly to invade and destroy healthy brain tissue, and sends out cancerous tendrils into the brain that make surgical tumor removal extremely difficult or impossible.

When standard cancer treatments like surgery, chemotherapy, and radiation cease to be effective, doctors increasingly turn to immunotherapy, which encourages the body’s own immune cells to seek and destroy cancer cells. Though not universally effective, ICB immunotherapy has shown “impressive clinical efficacy” for many tumors, the investigators noted, and has provided many patients with strong, long-lasting anticancer responses. However, immunotherapies have demonstrated limited efficacy against glioblastoma, which the team noted highlights “… the need to better understand the nature of the immune response to glioblastoma, what types of immune responses may provide protection against glioblastoma, and how this will vary across the different glioblastoma subtypes.”

Kaech and colleagues set out to investigate new ways of harnessing the immune system to develop more safe and durable treatments for brain cancer, and focused on a mouse model of mesenchymal-like (MES-like) glioblastoma, which in humans is the most aggressive subtype of the disease.

From left: Susan Kaech, Dan Chen, and Siva Karthik Varanasi. [Salk Institute]
From left: Susan Kaech, Dan Chen, and Siva Karthik Varanasi. [Salk Institute]

The team’s studies in mice found that three cancer-fighting tools—anti-CTLA-4 immunotherapy, CD4+ T cells and microglia—which have been somewhat overlooked in brain cancer research, may cooperate and effectively attack glioblastoma. 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.

Anti-CTLA-4 immunotherapy works by blocking cells from making the CTLA-4 protein, which, when not blocked, inhibits T-cell activity. Anti-CTLA-4 immunotherapy was the first type of immunotherapy drug designed to stimulate the immune system to fight cancer, and was followed by another, anti-PD-1 treatment, that was less toxic and became more widely used. Whether anti-CTLA-4 might be an effective treatment for glioblastoma has remained unknown, as anti-PD-1 strategies took precedence in clinical trials. But unfortunately, multiple clinical trials found anti-PD-1 therapy to be ineffective against glioblastoma, a failure that inspired Kaech to see whether anti-CTLA-4 might be effective instead.

For their newly reported study, the researchers first compared the lifespans of mice with MES-like glioblastoma, following treatment with either anti-CTLA-4 versus anti-PD-1 antibodies. The results showed that blocking CTLA-4 significantly prolonged mouse lifespan, whereas blocking PD-1 did not. The next stage was to try and figure out why.

Further experiments showed that after anti-CTLA-4 treatment, CD4+ T cells secreted a protein called interferon-gamma (IFNγ) that caused the tumor to throw up “stress flags” while simultaneously alerting microglia to start engulfing and destroying the stressed tumor cells. As they gobbled up the tumor cells, the microglia would present scraps of tumor on their surface to keep the CD4+ T cells active and producing more IFNγ, creating a cycle that repeated until the tumor was destroyed. “We found that a protective response to αCTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells in MES-like glioblastomas,” the authors wrote.

To understand the role of microglia in this cycle, the researchers collaborated with co-author and Salk professor Greg Lemke, PhD, holder of the Françoise Gilot-Salk Chair. For decades, Lemke has investigated critical molecules, called TAM receptors, which are used by microglia to send and receive crucial messages. The researchers’ studies found that TAM receptors told microglia to destroy the cancer cells in this novel cycle.

“We were stunned by this novel codependency between microglia and CD4+ T cells,” said co-first author Siva Karthik Varanasi, PhD, a postdoctoral researcher in Kaech’s lab. “We are already excited about so many new biological questions and therapeutic solutions that could radically change treatment for deadly cancers like glioblastoma.” Added co-first author Dan Chen, PhD, a postdoctoral researcher in Kaech’s lab, “Our study demonstrates the promise of anti-CTLA-4 and outlines a novel process where CD4+ T cells and other brain-resident immune cells team up to kill cancerous cells.”

Connecting the pieces of this cancer-killing puzzle brings researchers closer than ever to understanding and treating glioblastoma. “We can now reimagine glioblastoma treatment by trying to turn the local microglia that surround brain tumors into tumor killers,” said 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.” The authors noted in their paper: “This microglia-CD4+ T cell crosstalk reveals an axis that enables robust protective anti-tumor immunity in preclinical models of glioblastoma and provides new insights for developing therapeutic strategies against human glioblastoma.”

Next, the researchers aim to examine whether this cancer-killing cell cycle is present in human glioblastoma cases. Additionally, they aim to look at other animal models with differing glioblastoma subtypes, expanding their understanding of the disease and optimal treatments. “Collectively, these findings demonstrate how CD4+ T cells can suppress glioblastoma in partnership with microglia, and therefore, we suggest that future clinical trials in glioblastoma should place more emphasis on αCTLA-4 ICB alone or with other therapies that stimulate CD4+ T cells and microglia,” they concluded.

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