TY - JOUR
T1 - Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy
AU - Wang, Xiaohong
AU - Schoenhals, Jonathan E.
AU - Li, Ailin
AU - Valdecanas, David R.
AU - Ye, Huiping
AU - Zang, Fenglin
AU - Tang, Chad
AU - Tang, Ming
AU - Liu, Chang Gong
AU - Liu, Xiuping
AU - Krishnan, Sunil
AU - Allison, James P.
AU - Sharma, Padmanee
AU - Hwu, Patrick
AU - Komaki, Ritsuko
AU - Overwijk, Willem W.
AU - Gomez, Daniel R.
AU - Chang, Joe Y.
AU - Hahn, Stephen M.
AU - Cortez, Maria Angelica
AU - Welsh, James W.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2017/2/15
Y1 - 2017/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-3142
DO - 10.1158/0008-5472.CAN-15-3142
M3 - Article
C2 - 27821490
AN - SCOPUS:85014004127
SN - 0008-5472
VL - 77
SP - 839
EP - 850
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -