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eSymposia | Myeloid Cells and Innate Immunity in Solid Tumors


Macrophage-associated genes to predict chemotherapy resistance in breast cancer patients


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

Description

Macrophage-associated genes to predict chemotherapy resistance in breast cancer patients Cigdem Selli1, Bin-Zhi Qian1 1 MRC Centre for Reproductive Health, College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK Rational: Gene expression profiles of breast tumours under neoadjuvant chemotherapy have been recently identified (NEO study) 1. In NEO study, those patients achieved a complete response were classified as “responder” whereas those with progressive disease were classified as “non-responder”. Tumours were sequentially biopsied and profiled at pre-treatment, early on treatment, mid-chemotherapy, and at surgical resection. It is well established that tumour-associated macrophages promotes chemotherapy resistance in preclinical studies 2. We propose that macrophage-associated genes can be used to pinpoint the lack of response to chemotherapy after a relatively short duration of treatment (2 weeks or mid-chemotherapy) contributing to the individualized treatment of patients and improving patient outcomes. Approach: To delineate macrophage-associated genes in chemotherapy resistance, we determined the macrophage-correlated genes specific to non-responder tumours in NEO study using R and Bioconductor. Macrophage abundance was estimated using ImSig, a computational approach to estimate immune cell abundance from gene expression 3. Mean expression of macrophage genes of ImSig and Pearson correlation were used to identify macrophage-associated genes in each group. Results: Macrophage abundance was similar across groups in all timepoints suggesting presence of a subset of tumour-associated macrophages rather than overabundance of macrophages drives therapy resistance. Based on this, top macrophage-correlated genes in each group were determined. Then, non-responder-specific genes were identified to determine resistance-driving macrophage-associated genes. Among these genes, those with significantly higher levels in non-responders compared to responders were determined as candidates. In addition, candidate genes were confirmed to be macrophage-specific by comparing with Human Protein Atlas data and literature search. Future perspectives: Candidate genes will be validated using gene expression data from I-SPY 1 trial 4 with a total of 248 sequential samples from responder and non-responder patients. Candidate genes will be further validated at protein level by staining using NEO study samples. This will allow identification of robust macrophage-associated genes allowing early prediction of lack of response to chemotherapy contributing to the timely detection of resistance development and better individualized treatment of patients. References 1. Bownes RJ et al 2019 Breast Cancer Res 21(1) 2. Ali HR et al 2016 Plos Med 13(12) 3. Nirmal AJ et al 2018 Cancer Immunol Res 6(11) 4. Magbanua MJ et al 2015 Breast Cancer Res 17

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