title: Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance.
abstract: 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.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Kinga B
authors.initials: KB
authors.lastname: Skowron
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.|Department of Surgery, Loma Linda University Health, Loma Linda, CA, USA.
authors.forename: Jukes P
authors.initials: JP
authors.lastname: Namm
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Burnette
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Fernandez
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Spiotto
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL, USA.
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.affiliation: The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.|Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.|The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003131:Combined Modality Therapy; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011878:Radiotherapy / Q000379:methods*; D016019:Survival Analysis; D014611:Vaccination / Q000379:methods*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D018925:Chemokines
keywords: T cell infiltration; checkpoint blockade; radiation therapy; tumor model; vaccination