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A preclinical study simulating "fight or flight" responses showed that reducing stress associated with the response improved tumor control, both locally and at distant sites, after radiation therapy.

Reducing β2-adrenergic receptor signaling with the beta-blocker propranolol was associated with a significant reduction in the growth of the primary irradiated tumor (P<0.01) as well as the growth of distant, nonirradiated tumors (P<0.0001). Administration of the beta-blocker alone also slowed primary tumor growth as compared with saline (P<0.01) but not as effectively as the combination or radiation alone. In animals that received the beta-blocker, decreased tumor growth was associated with reduced levels of the stress hormones epinephrine and norepinephrine.

Studies in T cell-depleted mice showed no effect of the beta-blocker or radiation therapy on either the primary tumor or distant, nonirradiated tumors, suggesting that radiation's effect on tumor growth (primary and distant or abscopal) depends on an intact immune system, as reported in .

"This opens up a whole host of new areas we can research and look at the impact on outcomes from cancer therapy," said coauthor Anurag K. Singh, MD, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York. "If you look at something as basic as the fight or flight response, when cave men were running away from tigers, it served a significant function. In today's society it gets activated for a variety of reasons ... and all of these things may end up impacting your care. We have started looking at all these other variables that we never considered before."

"Broadly speaking, we're looking at what are the stressors that patients experience and how do the stressors impact outcomes," he added. "That's something we wouldn't have had a molecular basis to look at prior to this. We can also look at ways to decrease the stress response."

Although the study focused on radiation therapy, the findings have implications for chemotherapy and other types of cancer treatment, Singh said.

Background

The results followed a series of laboratory studies that with the demonstration that exposure to mild cooling (22-23°C, 72-73°F) led to chronic adrenergic stress in mice, associated with sympathetic activation and release of norepinephrine. Other studies showed that chronic stress suppressed innate and accelerated and metastasis.

In contrast, housing animals at ~30°C (~86°F) led to significant reductions in chronic adrenergic stress and norepinephrine production and significant improvement in CD8+ T cell-dependent responses, the authors noted. Several groups have shown that adrenergic signaling increases tumor cell resistance to chemotherapy and targeted agents, and Singh and colleagues that temperature-induced adrenergic stress signaling increased tumor cell resistance to the antitumor effects of ionizing radiation.

The preceding work set the stage for studies to examine the relationship between housing temperature and the abscopal effects of ionizing radiation or the effects of adrenergic stress signaling on antitumor immunity after radiotherapy. Investigators conducted multiple experiments, assessing effects on both irradiated (primary) and nonirradiated (abscopal) tumors.

One set of studies evaluated the effects of temperature modulation. The combination of radiation and housing temperature of 30°C was associated with significantly less primary tumor growth versus radiation and housing temperature of 22°C, that either radiation condition suppressed tumor growth to a greater degree than temperature alone (30°C), and that higher temperature and the two radiation conditions reduced tumor growth as compared with the lower temperature alone.

With respect to abscopal tumor effects, the combination of radiation therapy and higher housing temperature led to significantly greater tumor growth suppression than all other conditions. Higher temperature alone preserved abscopal effects more effectively than did cooler temperature alone or with radiation therapy.

Another set of studies evaluated the effects of radiation with or without propranolol, the beta-blocker alone, and saline. Radiation plus propranolol was most effective at suppressing the primary and nonirradiated tumors (P<0.001). Propranolol alone was more effective than saline for controlling growth of the primary tumor.

A third set of experiments involved mice with severe combined immunodeficiency. Neither radiation therapy nor propranolol had an effect on primary or nonirradiated tumors, supporting the view that radiation's therapeutic effects depend on an intact immune system.

Finally, investigators evaluated the effects of propranolol and radiation therapy on tumors implanted in normal mice and in mice with a genetically engineered absence of β2-adrenergic receptors (knockout). The results showed that suppression of primary and nonirradiated tumors was similar in wild-type mice treated with propranolol and radiation and in irradiated knockout mice, regardless of whether the knockout mice received the beta-blocker. Taken together, the results suggested that adrenergic signaling is a critical pathway for radiation therapy effectiveness against irradiated and nonirradiated tumors.

Looking Ahead

In additional studies, Singh and colleagues explored possible mechanisms underlying the observed effects. They showed that CD8+ T cells, but not CD4+ T cells, are essential to radiation therapy's antitumor effects on primary and nonirradiated tumors, following inhibition of β2-adrenergic receptor signaling. They also found evidence that β2-adrenergic signaling blockade enhances T cell-mediated antitumor immune responses and reduces M2 macrophages, which are both immunosuppressive and tumor promoting.

Putting the findings into the context of cancer therapy, Singh told 乌鸦传媒視頻, "In the setting of cancer and cancer treatment, if you're under a lot of stress, and your beta-2 receptors are occupied with adrenaline and noradrenaline because you're stressed all the time, then that prevents the T cells from getting out of the tumor-draining lymph nodes, where they're growing and getting ready for battle and actually going into battle in the tumor."

The study provides a mechanistic rationale for using methods to disrupt beta-adrenergic signaling to enhance antitumor immune responses, including the abscopal response, said Encouse Golden, MD, of Weill Cornell Medicine in New York City. Previous retrospective studies have shown that patients with cancers treated with radiation therapy had better outcomes if they had a history of beta-blocker use.

"It has been assumed that effector T-cells re-enter the circulation (from lymph nodes) and go not only to the irradiated tumor but also distant tumors," he said. "What they are acknowledging in this manuscript is that this beta-adrenergic pathway sort of regulates the egress of the T cells from the tumor-draining lymph nodes. They are suggesting that blocking the beta-2 adrenergic response enhances the egress of the T cells from the tumor-draining lymph nodes."

The findings could provide support for future clinical trials to evaluate interventions aimed at enhancing the antitumor activity of radiation therapy, said Golden, an expert for the American Society for Radiation Oncology.

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