Enhanced Vaccine Immunogenicity Enabled by Targeted Cytosolic Delivery of Tumor Antigens into Dendritic Cells

Nicholas L Truex; Aurélie Rondon; Simon L Rössler; Cameron C Hanna; Yehlin Cho; Bin-You Wang; Coralie M Backlund; Emi A Lutz; Darrell J Irvine; Bradley L Pentelute

doi:10.1021/acscentsci.3c00625

Enhanced Vaccine Immunogenicity Enabled by Targeted Cytosolic Delivery of Tumor Antigens into Dendritic Cells

ACS Cent Sci. 2023 Sep 14;9(9):1835-1845. doi: 10.1021/acscentsci.3c00625. eCollection 2023 Sep 27.

Authors

Nicholas L Truex^{1

2}, Aurélie Rondon¹, Simon L Rössler¹, Cameron C Hanna¹, Yehlin Cho³, Bin-You Wang¹, Coralie M Backlund⁴, Emi A Lutz^{4

5}, Darrell J Irvine^{3

4

5

6

7}, Bradley L Pentelute^{1

4

8

9}

Affiliations

¹ Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
² Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States.
³ Department of Materials Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
⁴ The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States.
⁵ Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
⁶ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
⁷ Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, United States.
⁸ Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
⁹ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Abstract

Molecular vaccines comprising antigen peptides and inflammatory cues make up a class of therapeutics that promote immunity against cancer and pathogenic diseases but often exhibit limited efficacy. Here, we engineered an antigen peptide delivery system to enhance vaccine efficacy by targeting dendritic cells and mediating cytosolic delivery. The delivery system consists of the nontoxic anthrax protein, protective antigen (PA), and a single-chain variable fragment (scFv) that recognizes the XCR1 receptor on dendritic cells (DCs). Combining these proteins enabled selective delivery of the N-terminus of lethal factor (LF_N) into XCR1-positive cross-presenting DCs. Incorporating immunogenic epitope sequences into LF_N showed selective protein translocation in vitro and enhanced the priming of antigen-specific T cells in vivo. Administering DC-targeted constructs with tumor antigens (Trp1/gp100) into mice bearing aggressive B16-F10 melanomas improved mouse outcomes when compared to free antigen, including suppressed tumor growth up to 58% at 16 days post tumor induction (P < 0.0001) and increased survival (P = 0.03). These studies demonstrate that harnessing DC-targeting anthrax proteins for cytosolic antigen delivery significantly enhances the immunogenicity and antitumor efficacy of cancer vaccines.

Abstract

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