期刊
PLOS ONE
卷 16, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0251731
关键词
-
资金
- Canadian Institutes of Health Foundation [159912]
The study found that the use of HCQ alone or in combination with AZ reduced the therapeutic benefit of anti-PD-1 in cancer immunotherapy without causing harm to untreated tumors. Mechanistically, HCQ inhibited PD-L1 expression on tumor cells and the increase in TILs induced by anti-PD-1 treatment.
Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8(+)CD44(+)PD-1(+)TCF1(+) tumor infiltrating T cells (TILs) and the generation of CD8(+)CD44(+)PD-1(+) effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8(+) TILs. No effect was seen on the presence of CD4(+) T cells, FoxP3(+) regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.
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