title: Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity.
abstract: The anti-apoptotic function and tumor-associated expression of heat-shock protein 70 (HSP70) is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti-tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3(-/-)(Hsp70(-/-)) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70(-/-) murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immunodeficient hosts as efficiently as wild-type (WT) transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70(-/-) bone marrow and progression of B-cell leukemogenesis in vivo revealed no differences in disease onset or survival rates, and Eμ-Myc-driven lymphoma in Hsp70(-/-) mice was phenotypically indistinguishable from that in WT Eμ-Myc mice. However, Hsp70(-/-) E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6 J immune-competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8(+) T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Dodd
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nance
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Quezada
authors.affiliation: Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Janke
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Morrison
authors.affiliation: 1] Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA [2] PUMA Biotechnology, Los Angeles, CA, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Williams
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Beere
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D047368:Tumor Burden
chemical_list: D018840:HSP70 Heat-Shock Proteins; D016044:Fusion Proteins, bcr-abl