Multilevel Stressors and Systemic and Tumor Immunity in Black and White Women With Breast Cancer
Authors: Alexandra R. Harris, Catherine M. Pichardo, Jamirra Franklin, Huaitian Liu, William Wooten, Gatikrushna Panigrahi, Wayne R. Lawrence, Margaret S. Pichardo, Brittany D. Jenkins, Tiffany H. Dorsey, Olga B. Ioffe, Harry G. Yfantis, Tanya Agurs-Collins, Stefan Ambs
Journal: JAMA Network Open (2025)

Importance The mechanisms through which chronic stressors may be associated with tumor biologic characteristics, immune response, and health disparities remain insufficiently understood. Objective To investigate the proteomic, transcriptomic, and genomic effects associated with multilevel chronic stressors (perceived stress, perceived inadequate social support, perceived racial and ethnic discrimination, and neighborhood deprivation) in Black and White women with breast cancer. Design, Setting, and Participants This cross-sectional study was conducted from February 28, 2012, to September 5, 2023, in which blood samples, breast tumors, and adjacent noncancerous tissues were collected from women with breast cancer. Participants, recruited at 2 Baltimore, Maryland, hospitals, completed demographic and psychosocial questionnaires. Data analysis was conducted from September 2023 to April 2024. Exposures Perceived stress, perceived social support, perceived racial and ethnic discrimination, and the 2010 census tract-level neighborhood deprivation index, in which scores range from −2.51 to 6.77, with higher scores indicating greater deprivation. Main Outcomes and Measures The main outcomes included levels of 92 circulating immune-oncologic markers and associated biologic pathways, tumor immune cell profiles, breast tissue gene expression, and tumor mutational burden. Data were analyzed using covariate-adjusted linear regression modeling for continuous outcomes with effect estimates presented as β values with 95% CIs. Results The study included 121 women with breast cancer (mean [SD] age, 56.27 [12.62] years), of whom 56 (46.3%) were Black, and 65 (53.7%) were White. The analytic subsample sizes included 117 blood samples, 48 breast tumors, and 41 adjacent noncancerous tissues. Levels of perceived stress and social support were comparable by race, while Black women resided in more socioeconomically deprived neighborhoods (mean [SD] neighborhood deprivation index, 2.28 [2.30] for Black women compared with −0.22 [2.01] for White women). Greater perceived social support was associated with more favorable immune-stimulatory changes (eg, increased serum IL-5 [β, 0.06 (95% CI, 0.02-0.10); P = .003] and activated natural killer cells in noncancerous breast tissue of Black women [β, 0.11 (95% CI, 0.04-0.17); P = .002). Higher levels of perceived stress, exposure to discrimination, and neighborhood deprivation were associated with systemic inflammation (eg, serum IL-6 with both perceived stress [β, 0.04 (95% CI, 0.01-0.07); P = .006] and discrimination [β, 0.69 (95% CI, 0.15-1.23); P = .01]); deleterious immune cell profiles (eg, tumor-associated M2 macrophages with discrimination [β, 0.82 (95% CI, 0.14-1.51); P = .02]); and aggressive tumor biologic characteristics. Race-stratified analyses uncovered distinct immunologic features in Black women associated with stressors, including chemotaxis with stress (β, 0.28 [95% CI, 0.001-0.56]; P = .049) and immune suppression with stress (β, 0.37 [95% CI, −0.002 to 0.75]; P = .05) at the systemic level and increased tumor-associated myeloid cells (monocytes and M1 and M2 macrophages) at the tissue level. Perceived stress was associated with elevated tumor mutational burden (β, 0.02 [95% CI, 0.01-0.04]; P = .04). Conclusions and Relevance The findings of this cross-sectional study of Black and White women with breast cancer suggest that perceived stress, perceived inadequate social support, perceived racial and ethnic discrimination, and neighborhood deprivation were associated with deleterious alterations to the systemic and tumor immune environment, particularly for Black women. Understanding biology as a possible mediator of cancer health disparities may inform prevention and public health interventions.