[R01] Accelerated Biological Aging and Immunosenescence as Drivers for Racial Disparities in Monoclonal Gammopathy of Undetermined Significance (MGUS)
Ente: National Cancer Institute
Scadenza: 2031-04-30
Importo max: 558.016 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Multiple myeloma (MM) is an incurable plasma cell malignancy and the most common blood cancer among
individuals who self-identify as African American, accounting for ~20% of newly diagnosed cases. The biological
factors contributing to the increased risk of MM and its precursor condition, monoclonal gammopathy of
undetermined significance (MGUS), in individuals of African ancestry remain poorly understood. Strikingly,
when access to healthcare is equal, African American patients experience better clinical outcomes, and their
MM tumors exhibit lower genomic complexity compared to those of European American patients. It is well
established that the incidence of MGUS and MM increases with age, and aging is a primary determinant for
progression from MGUS to MM. African American patients are diagnosed with MGUS and MM at younger
average ages than European American patients, and emerging evidence suggests that individuals of African
ancestry exhibit accelerated biological aging and immunosenescence. Together, these observations suggest
that accelerated biological aging may contribute to the higher prevalence of MGUS and increased incidence of
MM in African Americans. In support of this, we found that African American patients with MGUS and MM, as
well as healthy donors, had increased CD57+ CD8+ T cells, a hallmark of immunosenescence. This altered
immune function may reduce tumor immune surveillance, decreasing the selective pressure that drives tumor
immunoediting. We hypothesize that individuals with predominant African ancestry who develop MGUS or MM
experience accelerated biological aging and immunosenescence compared to those with predominant
European ancestry, resulting in reduced tumor immunoediting and the development of tumors with less genomic
complexity- a feature linked to more favorable clinical outcomes. In Aim 1, we will assess whether patients with
MGUS and MM who have predominant African ancestry exhibit accelerated biological aging compared to those
with predominant European ancestry. In Aim 2, we will compare the immune tumor microenvironment in MGUS
and MM patients with predominant African ancestry vs. those with predominant European ancestry to test the
hypothesis that African ancestry patients exhibit increased immunosenescence. In Aim 3, we will evaluate
whether MM tumors from patients with predominant African ancestry exhibit reduced immunoediting relative to
those from patients with European ancestry. To mechanistically model this, we will use a mouse MM
tumorigenesis model and apply unpredictable chronic mild stress to mimic chronic environmental and
psychosocial stressors to test whether tumors arising under stress exhibit reduced immuno editing, evidenced
by decreased genomic complexity and the reduced ability to engraft in immunocompetent recipient mice.
Overall, this work will elucidate the role of accelerated biological aging and immunosenescence as potential
drivers for increased MM incidence in individua
Istituzione: MAYO CLINIC ROCHESTER
PI: LINDA B BAUGHN, Megan M. Weivoda
Progetto: 1R01CA313650-01
Settori: National Cancer Institute
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