Heat Shock Protein 90-Mediated Peptide-Selective Presentation of Cytosolic Tumor Antigen for Direct Recognition of Tumors by CD4+ T Cells

Abstract

Tumor Ag-specific CD4+ T cells play important functions in tumor immunosurveillance, and in certain cases they can directly recognize HLA class II-expressing tumor cells. However, the underlying mechanism of intracellular Ag presentation to CD4+ T cells by tumor cells has not yet been well characterized. We analyzed two naturally occurring human CD4+ T cell lines specific for different peptides from cytosolic tumor Ag NY-ESO-1. Whereas both lines had the same HLA restriction and a similar ability to recognize exogenous NY-ESO-1 protein, only one CD4+ T cell line recognized NY-ESO-1+ HLA class II-expressing melanoma cells. Modulation of Ag processing in melanoma cells using specific molecular inhibitors and small interfering RNA revealed a previously undescribed peptide-selective Ag-presentation pathway by HLA class II+ melanoma cells. The presentation required both proteasome and endosomal protease-dependent processing mechanisms, as well as cytosolic heat shock protein 90-mediated chaperoning. Such tumor-specific pathway of endogenous HLA class II Ag presentation is expected to play an important role in immunosurveillance or immunosuppression mediated by various subsets of CD4+ T cells at the tumor local site. Furthermore, targeted activation of tumor-recognizing CD4+ T cells by vaccination or adoptive transfer could be a suitable strategy for enhancing the efficacy of tumor immunotherapy.

Targeting Heat-Shock Protein 90 (HSP90) as a Complementary Strategy to Immune Checkpoint Blockade for Cancer Therapy

“…Indeed, as part of the classical endogenous pathway of antigen presentation, data from in vitro studies suggested that HSP90 may be required for the binding and delivery of chaperoned, antigenic peptides with MHC I molecules to the cell surface (29). More recently, it has been shown that HSP90 can also facilitate direct tumor recognition by CD4 þ T cells via a nonclassical, MHC IImediated mechanism for presentation of intracellular tumor antigens (30). HSP90 also plays pivotal roles in efficient antigen cross-presentation and priming by antigen donor cells (31,32), and in both the functional and phenotypic regulation of T lymphocytes (33).…”

Gamma-interferon-inducible lysosomal thiol reductase is upregulated in human melanoma

“…Melanoma cells, APCs and keratinocytes may contribute to MHC class II-restricted presentation in melanoma tumors. Melanoma cells may express MHC class II and are capable of presenting endogenous membrane bound and cytoplasmic antigens on MHC class II [14, 15]. Melanoma tumor cells directly presenting antigen are capable of activating naïve T cells [12].…”

The elucidation of non-classical MHC class II antigen processing through the study of viral antigens

“…As mentioned, targets of autoimmunity can be generated by chaperone-mediated autophagy [48] but endogenous processing has been reported for various autoantigens [64–68] and tumor antigens [69•,70]. If, as in the case of influenza, the majority of MHC-II-restricted self-peptides are produced by endogenous processing, systems that restrict candidate autoantigens to endosomal processing may miss opportunities for mechanistic insights and therapeutic strategies.…”