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SignificanceImmunosuppressive Foxp3-expressing regulatory T cells (Tregs) in tumor tissues are assumed to be clonally expanding via recognizing tumor-associated antigens. By single-cell RNA sequencing, we have searched for the molecules that are specifically expressed by such multiclonal tumor Tregs, but not by tumor-infiltrating effector T cells or natural Tregs in other tissues. The search revealed the chemokine receptor CCR8 as a candidate. Treatment of tumor-bearing mice with cell-depleting anti-CCR8 antibody indeed selectively removed multiclonal tumor Tregs without affecting effector T cells or tissue Tregs, eradicating established tumors with induction of potent tumor-specific effector/memory T cells and without activating autoimmune T cells. Thus, specific depletion of clonally expanding tumor Tregs is clinically instrumental for evoking effective tumor immunity without autoimmune adverse effects.

α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5N,6O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation. Ministerio de Economía y Competitividad SAF2016-76083-R, CTQ2015-64425-C2-1-R Junta de Andalucía FQM2012-1467 Japan Society for the Promotion of Science 17K10051