Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone

Abstract

Wells AD, Rai SK, Salvato MS, Band H, Malkovsky M. Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone. Scand J Immunol 1997;45:605-612 Presentation of cytosolic peptides in the context of major histocompatibility complex (MHC) class I antigen is crucial for immune recognition of virus-infected and malignant cells. This process, which is often defective in cancer cells, involves a series of cellular events which may be facilitated by heat shock proteins (molecular chaperones). To address the influence of chaperone function on the presentation of cytosolic peptides, we have utilized B16 melanoma cells (H-2 b ). These tumour cells are resistant to lysis by MHC class I-restricted cytotoxic T lymphocytes (CTL), due to a very low level of surface MHC expression. The authors found that stably transfected clones of B16 expressing a heterologous heat shock protein (Hsp65) exhibit significantly increased levels of MHC class I antigens on their surface, and are effectively lysed by alloreactive CTL. These MHC class I molecules can form functional MHC-peptide complexes which are recognized by virus-specific CTL. Moreover, mice immunized with Hsp65-expressing tumour cells, but not with control-transfected tumour cells, display a significantly increased resistance to a subsequent challenge with live, wild-type B16. Together, these results indicate that the suitable expression of a molecular chaperone can overcome a defect in MHC class I expression and antigen presentation, and suggest a novel approach to cancer immunotherapy.

Inhibitory effect of the polyinosinic‐polycytidylic acid/cationic liposome on the progression of murine B16F10 melanoma

“…Furthermore, the transfection of B16 with the K b molecule converts it into a strongly immunogenic tumor in vivo [26] and renders it susceptible to rejection by immunocompetent mice [27]. Likewise, stably transfected B16 clones expressing the heat shock protein Hsp65, a "molecular chaperone," manifest significantly elevated levels of the MHC class I molecule and are more easily lysed by alloreactive CTL [28]. Therefore, our present results demonstrate the potential of peritumoral injection of PIC liposome for the treatment of human malignant melanoma.…”

CD28, TNF Receptor, and IL-12 Are Critical for CD4-Independent Cross-Priming of Therapeutic Antitumor CD8+ T Cells

“…The similarities between the requirements for costimulatory molecules and inflammatory cytokines in our model and that for cross-priming by hsp are so striking that it raises the intriguing possibility that priming by a whole cell vaccine may occur through the hsp representation pathways. In fact, overexpression of hsp70 on B16 melanoma cells not only induced MHC class I expression on the tumor cell surface, it also rendered the B16 melanoma immunogenic (73)(74)(75). Combining this with the capacity of hsp gp96 to induce IL-12 and TNF-␣ (70, 71) provides a possible pathway for CD4-independent cross-priming of tumor-reactive CD8 T cells by dendritic cells (76).…”

Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

“…Another mechanism involves the release of HSPs complexed with endogenous tumor peptides from dying tumor cells and the transfer of these antigenic peptides to antigen-presenting cells that, in turn, stimulate tumor-speci®c T-cells (Albert et al, 1998;Srivastava et al, 1998). A third hypothesis suggests that over-expression of some HSPs could enhance the ability of tumor cells to process and present MHCclass I antigens directly to T-cells (Wells et al, 1998). Based on the potential role of HSPs in inducing a tumor-speci®c immune response, clinical trials are now in progress to test HSP-peptide complexes isolated from each patient's tumor as a vaccine (Srivastava, 2000).…”