The Adaptive and Innate Immune Responses to Inherited TP53 Breast Cancers in Li-Fraumeni Patients


ASPIRE Award (2021-Present)

Arnold Levine, PhD (Principal) Institute for Advanced Study; Mark Davis, PhD, Stanford University; David Malkin, MD, Hospital for Sick Kids; Raymond Kim, MD PhD, Princess Margaret Hospital; Judy Garber, MD, and Junne Kamihara, MD PhD, Dana Farber Cancer Institute; Joshua Schiffman, MD, Huntsman Cancer Institute; Mark Robson, MD, and Michael Walsh, MD, Memorial Sloan Kettering Cancer Center

The most common mutations across all cancer types occur in a gene called TP53, which is mutated in half of all cancers. TP53 is a master regulator of cell-cycle progression and has been dubbed the “guardian of the genome” for its role in quality control of DNA before cell division. When it is mutated, a main checkpoint in the cell cycle is lost, which predisposes cells to proliferate uncontrollably. Although for most cancer patients, TP53 mutations occur somatically, there are people who carry germline mutations in TP53 who have a disorder called Li-Fraumeni syndrome (LFS). As one allele of TP53 is mutated in all of these patients’ cells from birth, they are at an enormous risk of developing cancer, with lifetime rates of cancer occurrence over 70%. Notably, among women with LFS, their risk of developing breast cancer between the ages of 18 and 40 is about 90%.

How these breast cancers compare to breast cancer in patients without LFS is an open question. The current classification scheme used to molecularly characterize breast cancer includes hormone responsive breast cancer (HRBC) or triple negative breast cancer (TNBC). These classifications not only guide treatments, but also predict how well the cancer will respond to immune checkpoint blockade therapy, which boosts the ability of the body’s immune system to attack the tumor. However, how breast cancers from LFS patients compare to these in terms of immune responsiveness has not been addressed.

Arnold Levine is leading a team who are examining breast cancer samples from LFS patients to provide a picture of the immune response in these cancers. They are using immunohistochemical imaging to quantitate the levels of tumor infiltrating lymphocytes (TILs), measure the serum levels of over 40 immunological markers before, during, and after treatment, and determine the T-cell receptor sequences of TILs. By comparing these results to patients with TNBC and HRBC, they will establish the landscape of immune response in LFS breast cancer, which may lead to improved diagnostic and therapeutic options for these patients.

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