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Treatments for childhood cancers can be lifesaving — but they can come with a catch.
Survivors of pediatric cancers are at higher risk of getting age-related conditions, like heart disease and secondary cancers, at younger-than-average ages. Whether their immune systems also age more rapidly — and how this may contribute to the early onset of age-associated conditions — is an open question.
Fred Hutch Cancer Center and Seattle Children’s pediatric immunologist Kavita Dhodapkar, MD, MBBS, recently received a five-year, $3.7 million R01 from the National Institute on Aging, along with University of Alabama at Birmingham co-principal investigator Smita Bhatia, MD, MPH, to investigate how immune aging may influence long-term health outcomes in survivors of pediatric cancer.
“The idea that survivors of childhood cancer age faster has been suggested, but the impact on immune system is understudied,” Dhodapkar said. “The idea is to identify the patients who are getting immune aged, and also to find targets for therapy that can prevent immune aging.”
National Institutes of Health R01 awards are competitive grants that support focused, multi-year research projects with public health relevance and clear outcomes. Dhodapkar’s award will allow her to leverage samples from the Childhood Cancer Survivor Study, a well-characterized cohort of long-term survivors of childhood blood cancers, to determine whether their immune systems age more rapidly and how this could influence cardiovascular outcomes.
Exploring the link between immune dysfunction and accelerated aging
It’s already well known that as we age, our immune function declines. We become more vulnerable to infection and less responsive to vaccines. On top of this, Dhodapkar said, chronic, abnormal inflammation — another hallmark of immune aging — contributes to chronic, age-associated conditions like heart disease and frailty.
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“We know that our children who are survivors really do well in the first five to 10 years after treatment, for the most part,” said Dhodapkar, who studies the intersections between cancer and the immune system in pediatric cancers. “But studies from many groups have shown that as they age and become adults, they get chronic diseases we typically associate with older people.”
In previous work, Dhodapkar and her team showed that even before treatment, many children diagnosed with cancer had noticeable immune dysfunction. They found that an individual’s pre-treatment immune signature often predicted how their immune system looked after treatment, and that certain immune patterns were associated with higher-risk disease and poorer prognosis for certain types of leukemia.
“It suggested that maybe there is some kind of immune set point that these children come in with, and after chemotherapy, when their immune system recovers, it recovers back to somewhere in that set point,” Dhodapkar said.
She and her team also developed a strategy to measure an individual’s immune “age,” separate from their chronological age. They found that the immune systems of people who have survived childhood cancer often look many years older than their actual age.
Dhodapkar and her team have access to a well-characterized cohort of survivors of childhood cancer, some of whom have been followed for three or four decades. Her R01 will allow her to dig deeper into the complexities of the immune system in childhood cancer survivors and test whether their immune systems age more rapidly than average, and how this plays out. Dhodapkar and her team will begin by focusing on survivors of blood cancers and their cardiovascular outcomes.
As part of this work, Dhodapkar will explore whether different immune aging patterns that will associate with different health outcomes, meaning that someone who gets cardiovascular disease at an early age may have a different pattern of immune aging than someone who becomes frail faster.
Further, Dhodapkar hopes that these immune signatures will be more than biomarkers. The findings could help identify those most at risk of accelerated immune aging and perhaps point to targets or strategies to intervene and prevent or slow accelerated aging and development of chronic conditions.
“We’ll come up with a lot of questions,” Dhodapkar said, such as “are there certain populations we need to worry about and how do we take care of them as they age?”
