Immune and Metabolic Reprogramming Induced by Paclitaxel, Capecitabine and Eribulin in Breast Cancer: Insights into Therapeutic Targets

Hua-Hsin Hsiao,1,* Riya Patel,2,* Pawel Kalinski,3 Kazuaki Takabe,4 Marc S Ernstoff,5 Spencer R Rosario,1,6 Shipra Gandhi7 1Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; 2Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; 3Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; 4Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; 5ImmunoOncology, NCI Division of Cancer Treatment and Diagnosis, Bethesda, MD, 20892, USA; 6Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; 7Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA*These authors contributed equally to this workCorrespondence: Spencer R Rosario, Roswell Park Comprehensive Cancer Center, Elm & Carlton Street, Buffalo, NY, 14263, USA, Email [email protected] Shipra Gandhi, Roswell Park Comprehensive Cancer Center, Elm & Carlton Street, Buffalo, NY, 14263, USA, Email [email protected]: Chemotherapeutic agents are known to exert anti-tumor effects by not only invoking cytotoxic effects, but also by altering both the immune profile and metabolic milieu. These alterations to both the immune milieu and circulating metabolome may be leveraged for designing rationale drug combinations with immunotherapeutic agents, once chemotherapy fails.Patients and Methods: Using publicly available transcriptomic data for breast cancer (BC) patients treated with neoadjuvant chemotherapy (GSE162187), we assessed transcriptional alterations that coincide with response to chemotherapy. To further study the metabolic and immune alterations associated with chemotherapeutic resistance, plasma samples from BC patients treated with eribulin, paclitaxel and capecitabine were obtained and assessed via Metabolomics and Luminex, at time of progression as compared to baseline.Results: Transcriptomics analysis revealed enrichment of amino acid and lipid metabolic pathways, as well as immune pathways including B cells, complement cascade and T cells, in patients resistant to chemotherapy. To validate these findings and assess the differences among different chemotherapies, plasma samples were obtained at baseline and disease progression. Increases in IL-18; IL-22, amylin and IL-6 were observed at the time of disease progression on eribulin, capecitabine and paclitaxel, respectively. Metabolically, increases in docosahexaenoic acid and decreases in sphingomyelins; increases in triacylglycerides and decreases in fatty acids, and decreases in glutamic acid, lipids and phosphatidylcholines were observed on disease progression on eribulin, capecitabine and paclitaxel, respectively.Conclusion: Distinct patterns of metabolic and immune dysregulation were associated with resistance to eribulin, capecitabine and paclitaxel. Varied immune and metabolic profiles were specific to each of the three chemotherapies, representing potential novel, and individualized, points of therapeutic leverage.Keywords: chemoresistance, immune regulation, metabolism, metastatic breast cancer