Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy.
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 byin vivopassaging 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.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Xiaohong
X
Wang
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jonathan E
JE
Schoenhals
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ailin
A
Li
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
David R
DR
Valdecanas
Department of Otolaryngology Head and Neck Surgery, The Affiliated Baiyun Hospital of Guiyang Medical University, Guiyang Medical University, Guiyang, China.
Huiping
H
Ye
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Fenglin
F
Zang
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Chad
C
Tang
Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ming
M
Tang
Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Chang-Gong
CG
Liu
Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Xiuping
X
Liu
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sunil
S
Krishnan
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
James P
JP
Allison
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Padmanee
P
Sharma
Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Patrick
P
Hwu
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ritsuko
R
Komaki
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Willem W
WW
Overwijk
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Daniel R
DR
Gomez
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Joe Y
JY
Chang
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Stephen M
SM
Hahn
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Maria Angelica
MA
Cortez
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jwelsh@mdanderson.org.
James W
JW
Welsh
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology*
D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor