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Nat Commun ; 12(1): 346, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436641

RESUMO

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Linfócitos do Interstício Tumoral/imunologia , Mastócitos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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