Abstract
Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired cross-presentation in DCs is largely associated with defect in trafficking of peptide–MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues.
Highlights
Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy
Typical example of seven experiments is shown. g, i Proliferation of OT1 CD8+ T cells after stimulation with DC generated with GM-CSF (g) or FLT3 ligand (i)
Even when T cells with pre-determined specificity (TCR-T cells or CAR-T cells) are used, the immune responses to shared antigens depend on the ability of DC to cross-present tumor antigens
Summary
Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. Tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. This pathway is dependent on the transporter for antigen presentation (TAP), and peptide loading on MHC class I molecules occurs either in the endoplasmic reticulum (ER) or in the lumen of endosomes or phagosomes. Proteasome-dependent but TAP-independent mechanism of cross-presentation was described It appears to be operational when high doses of soluble antigens are used[4]. L Proliferation of antigen-specific CD8+ T cells after stimulation with sorted CD103+DCs. Cumulative results of three experiments are shown.
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