Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype which has poor clinical prognosis. This can be attributed to lack of expression of well-known breast cancer associated receptors, which are targets of existing chemotherapeutic or immunotherapeutic treatments. TNBC also has impaired antigen presentation in the form of reduced human leukocyte antigen (HLA) class I and class II expression. Therefore, studies which explore the tumour immunopeptidome of TNBC are relevant. Moreover, identifying chemotherapeutic and immunotherapeutic agents which might enhance HLA surface expression and diversify the peptide repertoire, thereby revealing new potential targets is critical for engaging anti-tumour immunity. Furthermore, extending this work in clinic, wherein we can perform antigen discovery and identify biomarkers which can indicate or predict a patient’s response to treatment is crucial. To achieve this, we explored the plasma immunopeptidome in TNBC patients who underwent neoadjuvant chemotherapy to identify TNBC specific and associated peptides and proteins.
In parallel, we used an immunopeptidomics approach to investigate how IFN-γ and neoadjuvant chemotherapy (paclitaxel and doxorubicin) reshape HLA-mediated antigen presentation in TNBC cell lines. HLA-bound peptides were profiled by mass spectrometry in two TNBC cell lines (MDA-MB-231 and BT-549). IFN-γ significantly increased HLA-I surface expression and expanded the immunopeptidome diversity, with greater responsiveness observed in the metastatic TNBC cell line MDA-MB-231 compared to primary cell line BT-549. In contrast, chemotherapy induced only subtle modulation in the peptide repertoire of MDA-MB-231. Paclitaxel had little impact on the immunopeptidomic landscape, whilst doxorubicin selectively increased the proportion of HLA-C-restricted peptides without expanding overall peptide antigen diversity. Interestingly, in patient plasma, longitudinal soluble HLA profiling revealed therapy-associated remodelling at both peptide and protein level in responders compared to non-responders to neoadjuvant chemotherapy.
Collectively, these findings suggest using an immunopeptidomics approach opens up new avenues of treatment not only in the form of identifying candidate targets for epitope-based cancer vaccines but also identifying biomarkers which can assist in monitoring treatment-induced alterations in patients via less invasive liquid biopsies.