Cancer is commonly treated with drugs called immune checkpoint inhibitors (ICIs), which promote the body’s immune system to attack cancer cells. In patients treated with ICIs, inflammation of the heart muscle (called myocarditis) is an off-target side effect that disproportionately affects women. Drs. Yutao Xi and Jie Cheng at The Texas Heart Institute have collaborated with Dr. Chunru Lin, Dr. Liuqing Yang, and others at The University of Texas MD Anderson Cancer Center and several other institutions to identify the cause of myocarditis in women treated with ICIs. They have recently published their seminal research findings in Science Translational Medicine, which provide important insight into the mechanism for how ICIs may cause myocarditis in women.

 

In their study, the researchers found that treating tumor-bearing mice with ICIs decreased expression of the gene encoding MANF in the heart, which is a protein with known cardioprotective properties. This observation was even more pronounced in female mice than in male mice and held true in the heart tissues of patients affected by ICI myocarditis. In addition, when MANF protein was injected into the hearts of mice with ICI myocarditis, cardiac function was improved, supporting a role for MANF in protecting against myocarditis. Importantly, the researchers also discovered that expression of the gene encoding MANF was positively regulated by female hormones. When mice were treated with a combination of ICIs and female hormones, MANF levels were increased, and the mice did not develop myocarditis. These findings point to a critical role for MANF in ICI myocarditis and suggest that hormonal therapy administered in combination with ICIs may be a way to overcome the tendency of women to develop myocarditis. In the future, these findings may also broaden the use of ICI therapy to benefit a wider range of patients with cancer.

 

“We hope that this collaborative research work can pave the way towards identifying women who are more susceptible to this deadly disease and that we can find a way to effectively overcome it without compromising the efficacy of immunotherapy,” said Dr. Chunru Lin, Associate Professor at The University of Texas MD Anderson Cancer Center and one of the study’s corresponding authors.

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Zhang Y, Sun C, Li Y, Qin J, Amancherla K, Jing Y, Hu Q, Liang K, Zhang Z, Ye Y, Huang LA, Nguyen TK, Egranov SD, Zhao Z, Wu A, Xi Y, Yao J, Hung MC, Calin GA, Cheng J, Lim B, Lehmann LH, Salem JE, Johnson DB, Curran MA, Yu D, Han L, Darabi R, Yang L, Moslehi JJ, Lin C. Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis. Sci Transl Med. 2022 Nov 2;14(669):eabo1981. doi: 10.1126/scitranslmed.abo1981.

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News Story By Nicole Stancel, PhD, ELS(D)

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