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Cancer Res. 2017 Feb 15;77(4):839-850. doi: 10.1158/0008-5472.CAN-15-3142. Epub 2016 Nov 7.

Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy.

Author information

1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Otolaryngology Head and Neck Surgery, The Affiliated Baiyun Hospital of Guiyang Medical University, Guiyang Medical University, Guiyang, China.
3
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jwelsh@mdanderson.org.

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.

PMID:
27821490
PMCID:
PMC5875182
DOI:
10.1158/0008-5472.CAN-15-3142
[Indexed for MEDLINE]
Free PMC Article

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