Glioblastoma, probably the most common and deadly type of brain cancer, grows rapidly to invade and destroy healthy brain tissue. The tumor sends out cancerous tendrils into the brain that make surgical tumor removal extremely difficult or unimaginable.

Now, Salk scientists have found the immunotherapy treatment anti-CTLA-4 results in considerably greater survival of mice with glioblastoma. Moreover, they found that this therapy was depending on immune cells called CD4+ T cells infiltrating the brain and triggering the tumor-destructive activities of other immune cells called microglia, which permanently reside within the brain.

Published in Immunity on August 11, 2023, the findings show the good thing about harnessing the body’s own immune cells to fight brain cancer and could lead on to more practical immunotherapies for treating brain cancer in humans.

There are currently no effective treatments for glioblastoma-;a diagnosis today is largely a death sentence. We’re extremely excited to seek out an immunotherapy regimen that uses the mouse’s own immune cells to fight the brain cancer and results in considerable shrinkage, and in some cases elimination, of the tumor.”

Professor Susan Kaech, senior creator and director of the NOMIS Center for Immunobiology and Microbial Pathogenesis

When standard cancer treatments like surgery, chemotherapy, and radiation stop to be effective, doctors increasingly turn to immunotherapy. Immunotherapy encourages the body’s own immune cells to hunt and destroy cancer cells. Though not universal, immunotherapy works on many tumors and has provided many patients with strong, long lasting anti-cancer responses. Kaech wanted to seek out latest ways of harnessing the immune system to develop more secure and sturdy treatments for brain cancer.

Her team found three cancer-fighting tools which have been somewhat missed in brain cancer research that will cooperate and effectively attack glioblastoma: an immunotherapy drug called anti-CTLA-4 and specialized immune cells called CD4+ T cells and microglia.

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 primary immunotherapy drug designed to stimulate our immune system to fight cancer, however it was quickly followed by one other, anti-PD-1, that was less toxic and have become more widely used. Whether anti-CTLA-4 is an efficient treatment for glioblastoma stays unknown since anti-PD-1 took precedence in clinical trials. 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 can be any different.

As for the specialized immune cells, CD4+ T cells are sometimes missed in cancer research in favor of the same immune cell, the CD8+ T cell, because CD8+ T cells are known to directly kill cancer cells. Microglia live within the brain full time, where they patrol for invaders and reply to damage-;whether or not they play any role in tumor death was not clear.

First, the researchers compared the life spans of mice with glioblastoma when treated with anti-CTLA-4 versus anti-PD-1. After discovering that blocking CTLA-4 prolonged their life spans considerably, but blocking PD-1 didn’t, the team moved on to work out what made that final result possible.

They found that after anti-CTLA-4 treatment, CD4+ T cells secreted a protein called interferon gamma that caused the tumor to throw up “stress flags” while concurrently alerting microglia to start out eating up those stressed tumor cells. As they wolfed up the tumor cells, the microglia would present scraps of tumor on their surface to maintain the CD4+ T cells attentive and producing more interferon gamma-;making a cycle that repeats until the tumor is destroyed.

“Our study demonstrates the promise of anti-CTLA-4 and descriptions a novel process where CD4+ T cells and other brain-resident immune cells team as much as kill cancerous cells,” says co-first creator Dan Chen, a postdoctoral researcher in Kaech’s lab.

To know the role of microglia on this cycle, the researchers collaborated with co-author and Salk Professor Greg Lemke, holder of the Françoise Gilot-Salk Chair. For many years, Lemke has investigated critical molecules, called TAM receptors, utilized by microglia to send and receive crucial messages. The researchers found that TAM receptors told microglia to gobble up cancer cells on this novel cycle.

“We were stunned by this novel codependency between microglia and CD4+ T cells,” says co-first creator Siva Karthik Varanasi, a postdoctoral researcher in Kaech’s lab. “We’re already enthusiastic about so many latest biological questions and therapeutic solutions that would transform treatment for deadly cancers like glioblastoma.”

Connecting the pieces of this cancer-killing puzzle brings researchers closer than ever to understanding and treating glioblastoma.

“We are able to now reimagine glioblastoma treatment by attempting to turn the local microglia that surround brain tumors into tumor killers,” says Kaech, holder of the NOMIS Chair. “Developing a partnership between CD4+ T cells and microglia is making a latest style of productive immune response that now we have not previously known about.”

Next, the researchers will examine whether this cancer-killing cell cycle is present in human glioblastoma cases. Moreover, they aim to take a look at other animal models with differing glioblastoma subtypes, expanding their understanding of the disease and optimal treatments.

Other authors include Toshiro Hara, Kacie Traina, Ming Sun, Bryan McDonald, Yagmur Farsakoglu, Josh Clanton, Shihao Xu, Lizmarie Garcia-Rivera, Thomas H. Mann, Victor Du, H. Kay Chung, Ziyan Xu, Victoria Tripple, Eduardo Casillas, Shixin Ma, Carolyn O’Connor, Qiyuan Yang, Ye Zheng, and Tony Hunter of Salk.

The work was supported by the National Institutes of Health (CA195613), Cancer Research Institute, Damon Runyon Cancer Research Foundation, and a National Cancer Center fellowship.

Source:

Journal reference:

Chen, D., et al. (2023) CTLA-4 blockade induces CD4+ T cell IFNγ-driven microglial phagocytosis and anti-tumor function in glioblastoma. Immunity. doi.org/10.1016/j.immuni.2023.07.015.