Abstract P4-06-16: Analysis of tumor infiltrating lymphocytes in three age categories of luminal B-like breast cancer patients and its correlation with lymph node involvement and systemic immunosenescence/frailty markers
Authors: Berben L , Hatse S , Kenis C , Dalmasso B , Smeets A , Vos H , Neven P , Floris G , Wildiers H 
Published: May 2019

Abstract
BACKGROUND Immunosenescence, the age-related decrease in immune competence, which is characterized by decreased adaptive immunity and increased low-grade inflammation. It may lead to altered tumor immunity. However, immunosenescence markers have not been correlated yet with tumor infiltrating leukocytes (TILs) nor with clinical frailty.
METHODS This is the first study that investigates how age affects the relation between systemic immunity and tumor microenvironment in early luminal B-like breast cancer (BC) in function of age. Luminal B-like BC was defined as grade II-III, ER+, HER2- on core biopsies at inclusion. Three distinct age categories of BC patients were chosen: 35-45 years (y) (N=15), 55-65y (N=19), ≥70y (N=31). Stromal TILs (sTILs) % were assessed according to published guidelines, on representative tumor sections. Further characterization of the TILs by immunohistochemistry, using the antibodies against CD3, CD4, CD8, CD5, CD20, CD68 and FOXP3, is currently ongoing. Immunosenescence was evaluated by looking at eleven inflammatory plasma cytokines and chemokines, circulating insulin-like growth factor-1 (IGF-1), T-cell p16INK4a expression, PBMC subset profiles and expression levels of twenty immune-related microRNAs. In the old age category, geriatric assessment was performed.
RESULTS With increasing age, sTILs % significantly decreased, concomitant with significantly increased plasma levels of several inflammatory cytokines (IL-1α, IL-6) and chemokines (IP-10, IL-8, MCP-1), intermediate monocytes, as well as T-cell p16INK4a expression. Significant age-related decrease was seen for plasma IGF-1, naïve CD8+ T-cells and CD8+ T-cells expressing CD27 and/or CD28. Four immune-related microRNAs showed significantly different expression levels between the age groups: miR-18a decreased with age, miR-155 increased with age, miR-19b and miR-20a peaked in the middle group. As expected, various correlations exist between the different blood immunosenescence markers. The % of sTILs showed weak negative correlations with IL-6, IL-8, IL-1α, MCP-1 and the % of regulatory T-cells. Additionally the % of sTILs and several makers of immunosenescence (MCP-1, miR-20a, miR-155, intermediate monocytes) correlated with components of the geriatric assessment (activities of daily living (ADL), mini nutritional assessment (MNA), mini–mental state examination (MMSE)) and with the Leuven oncogeriatric frailty score (LOFS) in the oldest group. Conversely, lymph node involvement was not associated with the % of sTILs nor with any blood aging biomarker.
CONCLUSION sTILs % and several blood immunosenescence markers significantly differ between young and older luminal B-like BC patients. Some of these markers correlated with markers of clinical frailty as well. These findings suggest that interactions between tumor cells and immune/inflammatory cells differ with age and therefore applicable immune biomarkers and approaches for immunotherapy may vary depending on patients' age.
Citation Format: Berben L, Hatse S, Kenis C, Dalmasso B, Smeets A, Vos H, Neven P, Floris G, Wildiers H. Analysis of tumor infiltrating lymphocytes in three age categories of luminal B-like breast cancer patients and its correlation with lymph node involvement and systemic immunosenescence/frailty markers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-16.