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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.  

Author information

Wang X1, Schoenhals JE1, Li A1, Valdecanas DR1, Ye H2, Zang F3, Tang C4, Tang M5, Liu CG6, Liu X6, Krishnan S4, Allison JP7, Sharma P8, Hwu P9, Komaki R4, Overwijk WW10, Gomez DR4, Chang JY4, Hahn SM4, Cortez MA1, Welsh JW11.​

1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

2Department of Otolaryngology Head and Neck Surgery, The Affiliated Baiyun Hospital of Guiyang Medical University, Guiyang Medical University, Guiyang, China.

3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

4Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

5Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

6Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

7Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

8Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

9Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

10Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

11Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jwelsh@mdanderson.org.