Radiotherapy May Briefly Limit Cancer-Killing Power of Lymphocytes

By Marilynn Larkin

February 07, 2022

NEW YORK (Reuters Health) - Radiotherapy may temporarily make treated cancer cells less susceptible to killing by natural killer (NK) and cytotoxic T cells, potentially affecting the efficacy of combination treatment with immunotherapy, researchers suggest.

"In many previous studies, it's been shown that radiotherapy can boost inflammation and aid the body's own immune attack on a tumor," Dr. Daniel Davis of the University of Manchester, UK, told Reuters Health by email. "Here, using several experiments in a lab dish, we found that irradiation of cancer cells surprisingly led to resistance against a particular type of immune attack for a brief time."

"It is crucial to point out that these experiments were mainly done in lab dishes, and so the results here should not be taken to guide medical practice," he noted. "Rather, these lab experiments highlight that we need to more deeply understand how irradiation affects immune system responses to cancer, not least because we need to determine the best possible way of combining radiotherapy with other kinds of cancer therapies such as checkpoint inhibitors or CAR T cells."

Dr. Davis and colleagues write in PNAS, "Unexpectedly, we found that X-ray irradiation of cancer cells induced significant resistance to NK cell killing. This was true across a wide variety of cancer-cell types as well as for antibody-dependent cellular cytotoxicity."

Their lab experiments showed that resistance appeared 72 hours after irradiation and persisted for two weeks. Resistance also occurred without radiotherapy, through cell-cycle arrest induced pharmacologically (with nocodazole and palbociclib).

Importantly, targeted cell irradiation did not affect multiple steps in NK-cell engagement, synapse assembly, and activation. Instead, it caused strong resistance to perforin-induced calcium flux and lysis.

Resistance also occurred in a bacterial toxin, streptolysin O, which is structurally similar to perforin. Irradiation did not affect the binding of pore-forming proteins at the cell surface, or membrane repair. Rather, it initiated a defect in functional pore formation, consistent with phosphatidylserine-mediated perforin inhibition.

In mouse experiments, radiotherapy also led to a significant reduction in NK cell-mediated clearance of cancer cells. Radiotherapy-induced resistance to perforin also constrained chimeric antigen receptor T-cell cytotoxicity.

"Together, these data establish a treatment-induced resistance to lymphocyte cytotoxicity that is important to consider in the design of radiotherapy-immunotherapy protocols," the authors conclude.

Dr. Ofer Mandelboim, a professor of molecular immunology at Hebrew University of Jerusalem whose lab focuses on NK cells, commented on the study in an email to Reuters Health. "In this elegant and careful work, the authors demonstrate that irradiation leads to reduced perforin-mediated sensitivity of the irradiated tumor cells," he said. "Therefore, it is clinically important, especially when combinations of radiotherapy and immunotherapy are considered."

"I would like to see whether similar observations will be detected in human tumors, and longer in-vivo experiments," he added. "Since phosphatidylserine is a ligand for the inhibitory receptor CD300a, I would like to know whether CD300a is also involved in the radiotherapy-mediated NK cell resistance."

SOURCE: PNAS, online January 18, 2022.