Thursday, May 2, 2024
5/2/2024
A developing body of preclinical evidence suggests that the integrity and composition of the tumor immune microenvironment (TIME) is highly plastic and is modulated by host lifestyle exposures. Unhealthful exposures including obesity, inactivity and a high fat diet can lead to a loss of CD8+ T cell effector function and tumor progression in preclinical breast tumor models, while healthful exposures, such as voluntary wheel running, can offset tumor growth and dysregulated conditions in the TIME leading to increased trafficking and enhanced func- tion of CD8+ T cells. Although emerging pre-clinical evidence is compelling, several gaps in epidemiological knowledge regarding the link among lifestyle factors, tumor immunity and BC outcomes remain. First, despite a suggestion to adhere to The American Institute for Cancer Research (AICR) and The Ameri- can Cancer Society (ACS) cancer prevention lifestyle guidelines after a cancer diagnosis, which lifestyle factors and whether they work together to impact BC outcomes has not been well established. Second, research on the role of lifestyles and immunity in BC patients has primarily focused on immune cell subsets in the circulating peripheral blood. To our knowledge, whether lifestyles are associated with distinct immune cell phenotypes in the breast TIME, the site most relevant for treatment response and BC prognosis, has remained uninvestigated. Building off the extant preclinical evidence and multiple lines of published and preliminary evidence from our group, we designed the current study to address these critical gaps in knowledge. Leveraging data from 1160 primary invasive BC patients enrolled in the Data Bank and BioRepository (DBBR) at Roswell Park, we devel- oped a composite lifestyle index score (LIS) reflecting adherence to seven cancer prevention recommendations from The AICR and The ACS including: 1) maintaining a healthy weight; 2) being physically active; 3) eating a variety of fruits and vegetables; 4) limiting red and processed meats; 5) limiting or avoiding sugar-sweetened beverages; 6) limiting or avoiding alcohol consumption; and 7) avoiding smoking. Our preliminary analyses re- veals that patients with the highest versus lowest LIS (e.g., tertiles) experience striking survival advantages. Based on these and other preliminary data, we formulated our central hypothesis that CD8+ T cell composition in the breast TIME mediates the observed association between the LIS and BC outcomes. To test this hypothesis, we will link detailed lifestyle data with multispectral immunohistochemical immune profiling from 1160 BC patients enrolled in DBBR with available FFPE tumor tissue to execute formal mediation pathway analyses via three Specific Aims. In aim 1, we will define associations of the LIS with CD8+ T cell composition in the breast TIME (cell densities, ratios and clusters of total CD8+ T cells, exhausted CD8+ T cells and activated CD8+ T cells). Next, in aim 2, we will identify associations of CD8+ T cell composition in the breast TIME with BC outcomes. In aim 3, we will delineate the contributions of CD8+ T cells in the TIME as biological intermediaries underlying the observed association between the LIS and BC outcomes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
