TY - JOUR
T1 - Established T cell-inflamed tumors rejected after adaptive resistance was reversed by combination STING activation and PD-1 pathway blockade
AU - Moore, Ellen
AU - Clavijo, Paul E.
AU - Davis, Ruth
AU - Cash, Harrison
AU - Van Waes, Carter
AU - Kim, Young
AU - Allen, Clint
N1 - Funding Information:
This work was supported by the Intramural Research Program of the NIH, NIDCD, project number ZIA-DC000087. R. Davis was supported through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. C. Allen received further support through the American Academy of Otolaryngology/American Head and Neck Society Duane Sewell Young Investigators Award.
Publisher Copyright:
© 2017 AACR.
PY - 2016/12
Y1 - 2016/12
N2 - Patients with head and neck squamous cell carcinoma harbor T cell-inflamed and non-T cell-inflamed tumors. Despite this, only 20% of patients respond to checkpoint inhibitor immunotherapy. Lack of induction of innate immunity through patternrecognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. Here, we demonstrate robust control of a T cell-inflamed (MOC1), but not non-T cell-inflamed (MOC2), model of head and neck cancer by activation of the STING pathway with the synthetic cyclic dinucleotide RP,RP dithio-c-di-GMP. Rejection or durable tumor control of MOC1 tumors was dependent upon a functional STING receptor and CD8 T lymphocytes. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo. Established MOC1 tumors were rejected and distant tumors abscopally controlled, after adaptive immune resistance had been reversed by the addition of PD-L1 mAb. These findings suggest that PD-1 pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity.
AB - Patients with head and neck squamous cell carcinoma harbor T cell-inflamed and non-T cell-inflamed tumors. Despite this, only 20% of patients respond to checkpoint inhibitor immunotherapy. Lack of induction of innate immunity through patternrecognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. Here, we demonstrate robust control of a T cell-inflamed (MOC1), but not non-T cell-inflamed (MOC2), model of head and neck cancer by activation of the STING pathway with the synthetic cyclic dinucleotide RP,RP dithio-c-di-GMP. Rejection or durable tumor control of MOC1 tumors was dependent upon a functional STING receptor and CD8 T lymphocytes. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo. Established MOC1 tumors were rejected and distant tumors abscopally controlled, after adaptive immune resistance had been reversed by the addition of PD-L1 mAb. These findings suggest that PD-1 pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity.
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U2 - 10.1158/2326-6066.CIR-16-0104
DO - 10.1158/2326-6066.CIR-16-0104
M3 - Article
C2 - 27821498
AN - SCOPUS:85016106531
SN - 2326-6066
VL - 4
SP - 1061
EP - 1071
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 12
ER -