title: Natural killer and NK-Like T-cell activation in colorectal carcinoma patients treated with autologous tumor-derived heat shock protein 96.
abstract: Heat shock proteins (HSPs) are involved in the activation of both adaptive and innate immune systems. Here, we report that vaccination with autologous tumor-derived HSP96 of colorectal cancer patients, radically resected for liver metastases, induced a significant boost of natural killer (NK) activity detected as cytokine secretion and cytotoxicity in the presence of NK-sensitive targets. Increased NK activity was associated with a raise in CD3-CD56+ NK and/or CD3+CD56+ NK-like T cells, displaying enhanced expression of NKG2D and/or NKp46 receptors. Up-regulated expression of CD83 and CD40 and increased interleukin-12 release on stimulation were observed in CD14+ cells from post-HSP96 peripheral blood mononuclear cells, suggesting an indirect pathway of NK stimulation by HSP96-activated monocytes. Additionally, CD3-CD56+ and CD3+CD56+ lymphocytes were found to undergo functional and phenotypic activation on in vitro exposure to HSP96 even in the absence of monocytes, supporting a potential direct activity of HSP96 on these cell subsets. This evidence was confirmed by the specific binding of FITC-conjugated HSP96 to a subset of both CD3-CD56+ and CD3+CD56+ cells in peripheral blood mononuclear cells from colorectal cancer patients. Altogether, these findings identify the activation of the NK compartment as an additional immunologic effect of autologous tumor-derived HSP96 administration in cancer patients.
authors.affiliation: Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pilla
authors.forename: Paola
authors.initials: P
authors.lastname: Squarcina
authors.forename: Jorgelina
authors.initials: J
authors.lastname: Coppa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Veronica
authors.initials: V
authors.lastname: Huber
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccalli
authors.forename: Gloria
authors.initials: G
authors.lastname: Sovena
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Chiara
authors.initials: C
authors.lastname: Castelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
mesh_terms: D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000097:blood / Q000276:immunology* / Q000628:therapy; D018572:Disease-Free Survival; D006360:Heat-Shock Proteins / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D006360:Heat-Shock Proteins; C484813:vitespin