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Natural Killer and NK-Like T-Cell Activation in Colorectal Carcinoma Patients Treated with Autologous Tumor-Derived Heat Shock Protein 96

Units of ¹ Immunotherapy of Human Tumors, ² Hepatobiliary and Gastro-Pancreatic Surgery, and ³ Biomedical Statistics, Istituto Nazionale Tumori, Milan, Italy and ⁴ Laboratory of Immunology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

Requests for reprints: Licia Rivoltini, Unit of Human Tumor Immunotherapy, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-2390-3245; Fax: 39-02-2390-2630; E-mail: licia.rivoltini{at}istitutotumori.mi.it.

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.

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