A series of study have identified
potential ways for reducing resistance
within the immune system to
radiotherapy for fighting cancer cells

Studies unveil measures for reducing resistance to radiotherapy in tumors

April 26, 2019
by John R. Fischer, Senior Reporter
A series of studies have outlined insights which may aid in reducing resistance within the immune system to radiation therapy for combating tumors.

The cause of such resistance in all three studies falls on Treg cells, immunosuppressant cells that prevent effector T cells from destroying healthy tissue. This function, however, also prevents the effector T cells killing cancer cells. Combined with other factors, the researchers found that reducing the amount of Tregs resulted in less resistance to radiotherapy, helping to make it a potent immunotherapeutic agent.

“The genomics and characteristics of the cancer cell still matter, but so does the surrounding tumor microenvironment,” Sana Karam, assistant professor of the department of radiation oncology at the University of Colorado, told HCB News. “In people, we are irradiating the cancer in its entirety and the effects will be on the tumor cells and other cells within the tumor. Some of these effects will be suppressive to the growth of cancer cells while others may not be. To be able to reach a point where we can talk about tumor eradication, we have to leverage the pros of radiation in suppressing tumor growth and overcome any tumor promoting properties.”

The stimulation of the immune system with radiotherapy to attack cancer cells throughout the body was first witnessed by radiation oncologists over a decade ago, prompting numerous attempts to replicate the actions and create systemic anti-cancer activity by combining radiotherapy with immunotherapy. Such attempts, however, have not been successful, even when employing triple therapy and different targeted strategies.

Alone, radiation therapy was not enough to destroy head and neck cancer models grown in mice in the first study. Treg depletion alone had the same outcome. When combined together, however, a potent reduction in tumors was observed, with radiation acting as stimulant that "turned on" the T effector cells of the immune system and enabled them to attack the cancer. The decrease in Tregs, meanwhile, prevented the cancer from "turning them off".

The approach is limited, due to there being no agent able to eradicate Tregs safely in humans. The study, however, may offer a possible solution by inhibiting communication between the proteins EphB4 and ephrinB2. Essential for neurogenesis in the developing brain, studies have revealed an up-regulation of both in various cancers, including head and neck, and pancreatic malignancies. Inhibiting the interaction between them reduces the growth of tumors, while depleting the number of T-regulatory cells.

The reasons behind this act of inhibition are explored in the third study, in which ephrinB2 inhibition was applied in models of pancreatic cancer. Such an approach with ephrinB2 has traditionally resulted in poor prognoses, but through collaboration with multiple partners, it was found that ephrinB2 inhibition reduces "fibrosis" in tumors by packing them less tightly with cross-linked collagen fibers.

As these fibers are known to make pancreatic tumors less permeable to anti-cancer drugs, less vulnerable to the immune system, and more likely to metastasize, their decrease reduces resistance and allows for an immune system, stimulated by radiotherapy, to be better able to attack and destroy cancer cells.

“By understanding how the Tregs enter the tumor, how T cells that are normally destined to become effector T cells are converted to Tregs, what the Tregs use to stay alive, and what attracts Tregs to the tumor, we hope to develop new generation Treg targets that can potentially synergize with radiation,” said Karam. “Equally important in solving this puzzle is understanding why certain tumors do not have Tregs while others do. Capitalizing on the diverse biological heterogeneity will not only be key to identifying new targets, but might give us a glimpse into identifying biomarkers of response to certain therapies.”

The findings of the first study were published in the Journal of the National Cancer Institute, while those of the second and third were published in Cancer Research and Clinical Cancer Research, respectively.