Triple negative breast cancer (TNBC; estrogen receptor-, progesterone receptor- and HER2-negative) is the deadliest sub-type of breast cancer. However, relative to other breast cancer sub-types, TNBCs can be found with many tumor infiltrating T cells. The presence of these T cells suggests a response to tumor-associated antigens. From this response, some of the tumor-specific T cells proliferate and differentiate into effector, central, or tissue-resident memory T cells. The central memory T cells are long-lived and can be found surveying the body for the offending antigens. It was recently shown by Dr. Borges and others that the risk of mortality from TNBC sharply decreases 5 years after diagnosis. However, it is unknown which patients will respond successfully to therapy and which patients will recur. Thus, there is an urgent need to determine how these T cells can be harnessed for future therapies. It is proposed here to identify shared T cell receptors of TNBC survivors of five or more years and patients undergoing therapy. The overall goal of the proposed research is to improve treatments for TNBC patients using a method recently developed by the Slansky and DeKosky labs. They performed studies using high throughput sequencing, and found a panel of TCRs common to HLA-A2+ breast cancer patients, but not healthy controls. The T cell receptors shared in tumors were also identified in the peripheral blood of these patients. The overall objective of this application is to use the repertoire of alpha-beta memory CD8 T cells to identify a shared T cell response among responder patients and to determine the influence of standard therapy on T cells. The central hypothesis addressed here is that common subsets of TCRs can be identified that are unique to the blood of women who have survived TNBC more than 5 years, but not blood of women who have recurred.
The specific aims to address this hypothesis are: (1) to identify T cell receptors of shared memory T cells from the blood of TNBC survivors, and (2) determine longitudinal changes in the memory T cell repertoire that correlate with a pathologic complete response after treatment. Using the T cell repertoire to understand the generation of long-term memory responses to TNBC may ultimately revolutionize treatment for TNBC, as it will provide the first steps toward identification of T cell receptors that may be used to determine antigens critical to maintaining disease-free survival and other therapies that can offer ongoing protection against recurrence for years into survivorship.
The proposed research is relevant to public health because the discovery of how T cells of the immune system respond to triple negative breast cancer and current treatments will provide rationale improvements to therapy. The proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce illness and ultimately lengthen life.
