title: CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy.
abstract: Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8(+) T cells restored combinatorial efficacy. Furthermore, ablation of CD8(+) T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8(+) CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8(+) T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: David R
authors.initials: DR
authors.lastname: Soto-Pantoja
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Arunima
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: William G
authors.initials: WG
authors.lastname: DeGraff
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. dr9y@nih.gov.
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D051928:CD47 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005354:Fibrosarcoma / Q000276:immunology; D053804:Granzymes / Q000276:immunology; D006801:Humans; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011836:Radiation Tolerance / Q000276:immunology*; D011878:Radiotherapy / Q000379:methods; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D053804:Granzymes