Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

Low albumin status is prevalent in advanced cancer patients, but the pathophysiology associated with this anomaly remains largely unexplored. To address this, we aim to search correlations of albumin levels with the transcriptome against peripheral blood mononuclear cells and the plasma metabolome within the same patients having metastatic breast cancers. We confirm that metastatic breast cancer patients exhibit low albumin levels in varying degrees without prominent systemic inflammation. Our data demonstrate that low albumin levels correlate with transcriptome signatures indicative of neutrophil activation and T-cell down-regulation, an immunosuppressive phenotype. We also find that immunoregulatory metabolites, such as arginine, are reduced in plasma in an albumin-correlated manner, further corroborating systemic immunosuppression. These results are verified using a mouse model of breast cancer. We conclude that low albumin status in metastatic breast cancer patients accompanies immunosuppressive phenotypes, which is likely unfavorable for anti-cancer immunotherapy and thus can be a cause of unsuccessful treatment outcomes. ### Competing Interest Statement KK: grants from TERUMO, Astellas, Eli Lilly, Kyoto Breast Cancer Research Network; consulting fee from Becton Dickinson Japan; honoraria from Eisai, Chugai, and Takeda; MT: grants from Chugai, Takeda, Pfizer, Taiho, JBCRG Assoc., KBCRN Assoc., Eisai, Eli Lilly, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI Technology, Luxonus, Shionogi, GL Science, and Sanwa Shurui; honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayaku, Devicore Medical Japan, Sysmex; Advisory Board of Daiichi-Sankyo, Eli Lilly, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net; Board of Directors of JBCRG Assoc., KBCRN, NPO org. OOTR, and JBCS Assoc; Associate Editor of the British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women's Cancer, Asian Journal of Surgery, Asian Journal of Breast Surgery. All remaining authors declare no conflicts of interest.