Grant Number:	1R01CA316160-01 Interpret this number
Primary Investigator:	Cowell, Lindsay
Organization:	Ut Southwestern Medical Center
Project Title:	Role of Allostatic Load in Immunotherapy Outcomes
Fiscal Year:	2026

Project Summary/Abstract Disparities in cancer outcomes reflect a multifaceted interaction between multiple characteristics of patients. Allostatic load (AL) – a composite of neuroendocrine, immune, metabolic, and cardiovascular parameters – represents accumulated, chronic stress responses. AL provides additional insight beyond individual socio- demographic and economic risk factors by capturing the synergy of multilayered and interactive variables that promote health gaps. Higher in vulnerable populations (including those of multiethnic and lower income communities), this metric has been associated with increased risk of cancer, other chronic diseases, and mortality. Notably, AL has not been studied in the context of cancer immunotherapy outcomes. Furthermore, immunotherapy clinical trials have enrolled patients across all populations, and the few studies examining multiethnic patients have suggested the possibility of inferior outcomes. Unlike any other anti-cancer therapy, immunotherapy relies on patient organ systems and physiology for clinical effects. Therefore, aspects of host immune function are likely central determinants of treatment efficacy and toxicity. However, research into clinical biomarkers for the selection and tracking of immunotherapy regimens has focused almost exclusively on tumor characteristics as opposed to patient characteristics and immune function. To address this critical gap in current knowledge, we have assembled an institutional immuno-oncology registry (N>700) featuring diverse patient populations, detailed clinical data, serial biospecimen collection, and various immunoregulatory assays. Through progressive stages of AL, shifts in stress hormones, inflammatory cytokine/chemokine profiles, immune cell subset composition and recirculation, downstream signaling intermediates, and variability in single-cell RNA sequences may correlate with immune status. We therefore hypothesize that elevated AL is associated with worse immunotherapy outcomes and underlying biological and immunological mechanisms. This will be evaluated through the following Specific Aims: (1) Determine the association between AL, patient characteristics, and immunotherapy outcomes, (2) Identify the correlation between AL and immune function by quantifying soluble mediators of stress and inflammation, and (3) Characterize the correlation between AL and immune cell status using a single-cell multiomics approach – single-cell RNA sequencing (scRNA-seq) and cell surface receptor protein profiling. We will leverage baseline, pre-treatment blood samples (of >700 immunotherapy registry patients), patient characteristics (demographic and socioeconomic), electronic health record data for clinical characteristics, stored biospecimens, and perform new assays to calculate the AL score for each registry patient. In summary, AL, a complex, multifactorial composite index of stress and social determinants, may provide biological and immunological insights into health gaps to develop improved personalized immunotherapeutic regimens for better immuno-oncology outcomes in patients across diverse populations.





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