Tumor Eradication by Cisplatin Is Sustained by CD80/86-Mediated Costimulation of CD8+ T Cells

摘要: Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that not completely understood. Here we show how the DNA-damaging drug cisplatin modulates immunity. At maximum tolerated dose (MTD), cured 50% of mice with established murine TC-1 or C3 tumors, which preclinical models human papillomavirus (HPV)-associated cancer. Notably, curative benefit relied entirely upon induction tumor-specific CD8+ T cells. Mechanistic investigations showed stimulated infiltration inflammatory antigen-presenting cells (APC) expressing relatively higher levels T-cell costimulatory ligands CD70, CD80, and CD86. Cell death triggered by was associated release at least 19 proteins in environment could act as damage-associated molecular patterns upregulate molecules, either alone concert, but responsible remain unknown. Essentially, effect abrogated lacking expression CD80 CD86 on APCs. Furthermore, treatment improved CTLA-4 blockade, increases availability CD80/86 to bind CD28. In contrast, there no CD27 stimulation, replaces CD70 interaction. MTD, cure rates also be increased vaccination synthetic long peptides, whereas cures achieved similar 80% MTD reduced side effects. Our findings reveal an essential basis for immunogenic properties cisplatin, mediated signals T-cell-dependent destruction. Cancer Res; 76(20); 6017-29. ©2016 AACR.