A brand new methodology for preventing ‘chilly’ tumors

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A new method for fighting 'cold' tumors

Photo credit: CC0 Public Domain

Not all cancer tumors are created equal. Some tumors, known as "hot" tumors, show signs of inflammation, which means that they are infiltrated with T cells, which are active against the cancer. These tumors are easier to treat because immunotherapeutics can then increase the immune response.

"Cold" tumors, on the other hand, have no T-cell infiltration, which means that the immune system does not step in to help. Immunotherapy is of little use in these tumors.

It is the latter type of tumor that researchers Michael Knitz and radiation oncologist and member of the University of Colorado Cancer Center, Dr. med. Sana Karam, in a new study published this week in the Journal for ImmunoTherapy of Cancer. Knitz and Karam worked with mouse models in Karam's head and neck cancer area, studying the role of T cells in treating tumors.

"We found that the cells that normally tell the T cell, 'Hey, this is a tumor – come and attack it' are being silenced," says Karam.

She and her team found that regulatory T cells (Tregs), a specialized type of T cell that suppresses the immune response, are essentially telling T cells to stop fighting cancer.

"Tregs normally serve as an important balance in a healthy immune system," says Knitz. "They prevent autoimmune diseases and slow down the T-cells if necessary. In many tumors, however, the Tregs are too numerous or overly suppressive, which brings the T-cell reaction to a standstill."

Using drugs that deactivate the Tregs can boost the immune response in patients with cold tumors, as can radiation treatment, which causes so many injuries that immune cells known as dendritic cells put regular T cells into combat mode.

However, this is only part of the story. The T cells need to know what to attack. "You need the radiation to cause injury and bring in the immune cells so that the tumor can be identified and targeted," says Karam, also an associate professor of radiation oncology at the University of Colorado School of Medicine. “In this way, the dendritic cells trigger the immune system to produce lots of T cells, much like a vaccine. Those T cells then return to the tumor to kill cancer cells. The parts are already there; they just need that The right signals. Activating the dendritic cells is a critical step so that the radiation can heat these cold tumors. "

Importantly, Karam and her team, which includes postdoc Thomas Bickett, have determined that the radiation must be administered in a certain way.

"A certain dosage is required," says Karam. "You have to pulse it. You can't just give a dose. You have to give it again and combine it with things that break the suppression – the Tregs – while keeping those antigen-presenting dendritic cells active and on board."

Karam says the next step in her research is clinical trials that she hopes will change the treatment paradigm from surgery and weeks of chemotherapy and radiation to just three sessions of radiation and immunotherapy and then surgery. She says she is eager to change the standard for treating cold tumors because of the dire effects they have on patients.

"These tumors are similar to those found in patients who smoke heavily," she says. "They're very damaging to bones and muscles, and they infiltrate the tongue, jaw, gums and lymph nodes. It's terrible. We have very high failure rates with them, and treatment often involves removing the tongue and weeks of radiation and chemotherapy … just to give the patient." failed. I am confident we can do better for our patients. "

Beyond PD-L1: Removal of TIM3 and Tregs will stop cancer regrowth after immunotherapy

More information:
Michael W. Knitz et al., Targeting Resistance to Radiation Immunotherapy in Cold HNSCCs by Modulating the Treg Dendritic Cell Axis, Journal for ImmunoTherapy of Cancer (2021). DOI: 10.1136 / jitc-2020-001955

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CU Anschutz Medical Campus

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