Fighting a tumor is a marathon, not a sprint. For cancer-fighting T cells, sometimes the race is too long and the T cells stop fighting. Researchers even have a name for this phenomenon: T cell depletion.

In a new Natural immunology study, researchers at the La Jolla Institute of Immunology (LJI) report that T cells can be modified to clear tumors without succumbing to T cell depletion.

The idea is to give the cells a bit of armor against the exhaustion program. Cells can enter the tumor to do their job, and then they can stay as memory cells. “

Patrick Hogan, Ph.D., Professor LJI

This research builds on a decades-long collaboration between Hogan and Professor LJI Anjana Rao, Ph.D. Their work has shown the key role of proteins called transcription factors in the cellular pathway that triggers T cell depletion.

This work is important because T cell depletion continues to strain even the most advanced cancer immunotherapies.

With CAR T therapies, for example, researchers take T cells from a cancer patient and “arm” them by altering the expression of genes that help fight cancer. Researchers make more of these special T cells, which then return to the patient. CAR T therapies are different from immunotherapies, which aim to activate the patient’s existing T cell population.

With both approaches, T cell depletion occurs. “A lot of people have tried using CAR T therapies to kill solid tumors, but this has been impossible because the T cells are depleted,” says Hyungseok Seo, Ph.D., co-first author of the study, former Rao Lab postdoctoral fellow. currently works at Novartis.

The new study addresses this problem by empowering T cells to fight exhaustion on their own.

To do this, the researchers screened T cells to find out which transcription factors could stimulate a T cell’s “effector” program, an important step in preparing T cells to kill cancer cells.

This selection process led the researchers to BATF, a transcription factor that they say cooperates with another transcription factor called IRF4 to counter the T cell depletion program.

In mouse melanoma and colorectal carcinoma models, modification of CAR T cells to also overexpress BATF led to tumor clearance without causing depletion of T cells. CAR T therapy worked against solid tumors.

“BATF and IRF4 work together to improve T cells,” says Seo.

Further testing has shown that while IRF4 is important, it should not be overexpressed to the same degree as BATF. For maximum effect, BATF was overexpressed about 20 times more than in normal cells.

Encouragingly, some altered T cells also stuck together and became memory T cells. This is important because T cell depletion often prevents T cells from developing a strong memory response to recurrent cancers.

“We not only increased the ability of T cells to fight exhaustion, we increased the capacity of cells to fight tumors,” says co-first author of the study Edahí González-Avalos, a student graduate of the Rao laboratory who led the bioinformatics study analysis for the project.

Hogan believes that the overexpression of BATF could be a promising approach to improve CAR T therapies and to fight against certain difficult-to-treat types of cancer, such as pancreatic ductal carcinoma. These types of cancers are known as “immunologic cold” because they do not trigger a strong anti-cancer response from the immune system. T cells do not fight them with force.

Other labs have explored ways to make these cold tumors ‘hot’ so that they attract T cells. The LJI team believes that a promising strategy would combine these approaches with targeting transcription factors to make cells T proof against exhaustion.

“We wouldn’t necessarily need a transgenic approach to do this,” Hogan explains. “Maybe even an oral drug molecule could do it, if you knew what transcriptional pathways you wanted to follow.”

The researchers point out that BATF is only one of many transcription factors that may be important to manipulate to combat T cell depletion.

“We will continue to look for answers,” adds González-Avalos.

Source:

Journal reference:

Seo, H., et al. (2021) BATF and IRF4 cooperate to counter the depletion of CAR T cells infiltrating the tumor. Natural immunology. doi.org/10.1038/s41590-021-00964-8.



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