Camille Le Gall reports an efficient approach for delivery of poorly soluble tumor antigens to human cDC1s

Camille le Gall and colleagues from theme Nanomedicine published in the Journal of Immunotheraphy of Cancer that the efficient targeting of NY-ESO-1 tumor antigen to human cDC1s by lymphotactin results in cross-presentation and antigen-specific T cell expansion.

Conventional dendritic cells type 1 (cDC1s) excel at antigen cross-presentation, optimal for eliciting specific cytotoxic immune responses. This characteristic makes cDC1s ideal target cells for targeted vaccine cargo delivery. However, cDC1s are the rarest subset of dendritic cells (DCs), representing only 0.03% of human peripheral blood mononuclear cells (PBMCs), making them difficult to study. At the department of tumor immunology we have the expertise to isolate cDC1s in sufficient numbers via donor apheresis.

The cDC1s uniquely express X-C motif chemokine receptor 1 (XCR1), which binds and internalizes the chemokine XCL1. We made a site-specifically modifiable human XCL1 derivative for the modular conjugation of tumor antigens, such as the tumor-associated antigen NY-ESO-1 (157-165). Unfortunately, these peptide epitopes are notoriously poorly soluble, complicating the generation of peptide-based vaccines, often resulting in insoluble products. We solved this problem by linking a 5 kDa polyethylene glycol (PEG5k) to the peptide before conjugation to XCL1. Surprisingly, this PEGylation of the XCL1 - NY-ESO-1 peptide conjugate does not interfere with XCR1 binding on primary human cDC1s. This binding results in antigen uptake, antigen cross-presentation and subsequent activation of NY-ESO-1-specific T cell. We thus present a versatile modular platform to generate human cDC1-targeted vaccines applicable to a variety of typically poorly soluble tumor antigens.

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