Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance
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Wenxin Zheng1,3,*, Kinga B. Skowron2,3,*, Jukes P. Namm2,3,4,*, Byron Burnette1,3, Christian Fernandez1,3, Ainhoa Arina1,3, Hua Liang1,3, Michael T. Spiotto1,3, Mitchell C. Posner2, Yang-Xin Fu3,5, Ralph R. Weichselbaum1,3
1Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA
2Department of Surgery, University of Chicago, Chicago, IL, USA
3The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA
4Department of Surgery, Loma Linda University Health, Loma Linda, CA, USA
5Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
*These authors contributed equally to this work
Ralph R. Weichselbaum, email: firstname.lastname@example.org
Yang-Xin Fu, email: email@example.com
Keywords: checkpoint blockade, T cell infiltration, radiation therapy, vaccination, tumor model
Received: April 14, 2016 Accepted: May 20, 2016 Published: June 07, 2016
The majority of cancer patients respond poorly to either vaccine or checkpoint blockade, and even to the combination of both. They are often resistant to high doses of radiation therapy as well. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced poor outcomes. We developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi cancers. Tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation individually. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that sequential combination of radiation, vaccination and checkpoint blockade converts non-T cell-inflamed cancers to T cell-inflamed cancers, and mediates regression of established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This study has opened a new strategy for shifting “cold” to hot tumors that will respond to immunotherapy.
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