Abstract：
:Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53R172HΔg/+K-rasLA1/+ ) in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies. PD-L1 (CD274) expression did not differ between the resistant and parental tumor cells. However, the expression of important molecules in the antigen presentation pathway, including MHC class I and II, as well as β2-microglobulin, were significantly downregulated in the anti-PD-1-resistant tumors compared with parental tumors. Resistant tumors also contained fewer CD8+ (CD8α) and CD4+ tumor-infiltrating lymphocytes and reduced production of IFNγ. Localized radiotherapy induced IFNβ production, thereby elevating MHC class I expression on both parental and resistant tumor cells and restoring the responsiveness of resistant tumors to anti-PD-1 therapy. Conversely, blockade of type I IFN signaling abolished the effect of radiosensitization in this setting. Collectively, these results identify a mechanism of PD-1 resistance and demonstrate that adjuvant radiotherapy can overcome resistance. These findings have immediate clinical implications for extending the efficacy of anti-PD-1 immune checkpoint therapy in patients. Cancer Res; 77(4); 839-50. ©2016 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Wang X,Schoenhals JE,Li A,Valdecanas DR,Ye H,Zang F,Tang C,Tang M,Liu CG,Liu X,Krishnan S,Allison JP,Sharma P,Hwu P,Komaki R,Overwijk WW,Gomez DR,Chang JY,Hahn SM,Cortez MA,Welsh JWdoi
10.1158/0008-5472.CAN-15-3142subject
Has Abstractpub_date
2017-02-15 00:00:00pages
839-850issue
4eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-15-3142journal_volume
77pub_type
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