Andrianopoulou, Angeliki Danai; (2025) HER2 Antibody-Drug Conjugate (ADC)-Enhanced HER2-PD-L1 Association in HER2-Positive Breast Cancer. Doctoral thesis (Ph.D), UCL (University College London).

Text Andrianopoulou_Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2027. Download (4MB)

Abstract

HER2-positive breast cancer (HER2+ BC) represents around 25% of breast cancer cases. Although anti HER2 therapies have improved treatment outcomes, recurrence remains common in the metastatic setting, highlighting the need for new therapies and combination approaches. Recent early clinical trials suggest a potential role for immunotherapy, with PD-L1 emerging as both a target and potential biomarker for patient selection. In this study, I investigated the effect of anti-HER2 treatments on the immune checkpoint landscape in HER2+ BC cells. I discovered that T-DM1, an anti-HER2 antibody-drug conjugate (ADC), upregulated PD-L1 even in the absence of immune cells, a phenomenon not observed with trastuzumab alone. Immunofluorescence microscopy revealed that upregulated PD-L1 co-localised with HER2 in vesicular structures. I subsequently used proximity ligation assay (PLA) to confirm HER2-PD-L1 association following T-DM1 treatment. By combining PLA with direct immunofluorescence, I showed that HER2- PDL1 PLA signal localised to LC3- and transferrin receptor (TfR)-positive vesicles, indicative of autophagosomes and recycling endosomes, respectively. While investigating the underlying mechanisms of the T-DM1-induced effects, I demonstrated that CMTM6, previously reported to promote PD-L1 recycling, positively regulated the HER2-PD-L1 association. By perturbing autophagy, proteasomal, and lysosomal degradation pathways, I found that PD-L1 upregulation and HER2-PD-L1 association were partially dependent on these pathways. To assess the clinical relevance of my findings, I expanded this work to include taxane-based chemotherapeutic agents, which also induced HER2-PDL1 association in HER2+ BC cells. PLA analysis of patient tumour samples from the HERdi PREDICT study showed variable levels of HER2-PD-L1 association, even in diagnostic pre-treatment samples. Correlating tissue HER2-PD-L1 PLA signal with patient responses was limited by sample size and incomplete clinical data, but preliminary analysis suggested potential predictive value for the association of HER2 with PD-L1. Further research is required to understand the functional significance of the association and delineate its potential as predictive biomarker.

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