Poster Presentation 36th Lorne Cancer Conference 2024

Age-dependent changes in peripheral T cell phenotypes of early-stage breast cancer patients (#145)

Stefanie Stirl 1 2 , Michael L. Hun 1 2 , Kylie A. Clarke 1 , Megan M.R. O'Malley 1 2 , Luis E. Lara Gonzalez 1 2 , Michael A. Harris 1 2 , Jasmine Kay 1 2 , Valerie Setiono 1 , Paul Neeson 1 2 , Phillip K. Darcy 1 2 , Sherene Loi 1 2
  1. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia

 

Background:

Older age is associated with decreased immune function but younger patients present with more aggressive, higher-grade breast cancer (BC)1, and poorer response to immune checkpoint blockade2. We therefore investigated age-related differences in systemic immunity of early-stage breast cancer patients.

Methods:

We collected peripheral blood mononuclear cells (PBMCs) from 132 early-stage BC patients, and subdivided them into young (≤39 years), middle-aged (40-59 years), and older (≥60 years) groups. Age-matched healthy donors were also analysed (n=15 per group). We investigated peripheral blood immune phenotypes of patients by age with multiparameter flow cytometric analysis, and correlations between peripheral blood and tumour through T cell receptor sequencing (TCR-seq) using genomic DNA.

Results:

Median age of our patient cohort was 48 (range 24-83), with 32 young (24%), 75 middle aged (57%), and 25 older (19%) patients. Subtype distribution was predominantly ER+/HER2- (51%), with samples mostly node positive (52%) and grade 3 (70%), and a median tumor size of 27.5 mm. Flow cytometry data showed significantly more CD8+ memory T cell subsets with older age (P<0.0001). Moreover, an increased inflammatory phenotype with significantly higher IFN-γ+ and TNF-α+ CD8+ T cells in older BC patients compared with healthy donors (TNF-α P=0.01) and younger BC patients (P<0.0001; both TNF-α and IFN-γ) was observed. There was also significantly decreased PD-1 expression in peripheral blood CD8+ T cells in older BC patients compared to their healthy counterparts (P=0.03). Through TCR-seq analysis, we identified a 10.5 fold increase in peripheral hyperexpanded TCRs (P<0.0001) and a 57% increase in overlap of TCRs from tumour-enriched clones and PBMCs (P=0.03) in older patients (n=6) compared with young (n=5). Clonal expansion of virus-specific T cells (e.g. EBV and CMV) in breast tumour tissue was also observed in both young and older patients. Due to low power, we did not segregate by subtype.

Conclusions:

This study revealed significant differences in peripheral T cell immune responses to early-stage breast cancer with age which may account for the differential responses observed in young and older patients to immune checkpoint blockade. Further phenotypic and functional analysis of T cells from patients’ tumours is clearly warranted.  

 

  1. Kim, H. J., Kim, S., Freedman, R. A. & Partridge, A. H. The impact of young age at diagnosis (age below 40 years) on prognosis varies by breast cancer subtype: A U.S. SEER database analysis. Breast 61, 77-83, doi:10.1016/j.breast.2021.12.006 (2022).
  2. Adams, S. et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol 30, 405-411, doi:10.1093/annonc/mdy518 (2019).