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Promoting Antigen Escape from Dendritic Cell Endosomes Potentiates Anti-Tumoral Immunity

57 Pages Posted: 21 Jun 2021 Publication Status: Published

See all articles by Jean Pierre Bikorimana

Jean Pierre Bikorimana

University of Montreal - Department of Microbiology, Infectious Diseases and Immunology

Natasha Salame

Université de Montréal - Department of Biomedical Sciences

Simon Beaudoin

Defence Therapeutics Inc - Research and Development Branch

Mohammad Balood

University of Montreal - Department of Pharmacology and Physiology

Théo Crosson

University of Montreal - Department of Pharmacology and Physiology

Sebastien Talbot

University of Montreal - Department of Pharmacology and Physiology

Raimar Loebenberg

University of Alberta; University of Alberta - Faculty of Pharmacy and Pharmaceutical Sciences

Sebastien Plouffe

Defence Therapeutics Inc - Research and Development Branch

Moutih Rafei

University of Montreal - Department of Pharmacology and Physiology

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Abstract

Background: Dendritic cells (DCs) are usually very efficient at activating CD8 T cells. However, their capacity to cross-present soluble antigens can be limited by non-specific degradation of captured antigens during endosome maturation, which would lead to the destruction of immunogenic epitopes. To bypass this limitation, we tested a new antigen formulation using AccumTM, a technology originally designed to enhance accumulation of antibody-drug conjugate in target cells by promoting endosome-to-cytosol escape.

Methods: Following chemical linking and characterization of the Accum-antigen complex, a series of in vitro antigen presentation assays were conducted to assess the T-cell activation potency of the antigen formulation. The generated cellular product was then tested in vivo for its capacity to elicit anti-tumoral responses in both prophylactic and therapeutic vaccination settings. Finally, allogeneic DCs pulsed with tumor lysate linked to AccumTM were characterized for their therapeutic potency. 

Results: Linking the Accum moiety to the experimental xenoantigen ovalbumin caused endosomal damages resulting in enhanced intracellular protein processing by primary DCs. As a result, production of pro-inflammatory cytokines and chemokines was enhanced by responding T cells. When evaluated for their anti-tumoral properties, Accum-ovalbumin-pulsed DCs elicited potent effector and central memory CD8 T cells, which explains the complete and long-lasting protection observed in vaccinated mice despite multiple EG.7 T-cell lymphoma challenges. When combined with the anti-PD-1 immune checkpoint inhibitor, therapeutic vaccination using both syngeneic and allogeneic DCs pulsed with Accum-linked ovalbumin triggered potent anti-tumoral responses; an observation further enhanced using Accum-linked lymphoma tumor lysate proteins.

Conclusion: These highly favorable therapeutic effects highlight the promising potential of AccumTM as a distinct and potent technology platform suitable for the design of next generation cell cancer vaccines.

Keywords: Dendritic cells; Endosomes; AccumTM; Antigen Cross-Presentation; Anti tumoral Immunity; Immune Checkpoint Inhibitors

Suggested Citation

Bikorimana, Jean Pierre and Salame, Natasha and Beaudoin, Simon and Balood, Mohammad and Crosson, Théo and Talbot, Sebastien and Loebenberg, Raimar and Plouffe, Sebastien and Rafei, Moutih, Promoting Antigen Escape from Dendritic Cell Endosomes Potentiates Anti-Tumoral Immunity. Available at SSRN: https://ssrn.com/abstract=3871400 or http://dx.doi.org/10.2139/ssrn.3871400
This version of the paper has not been formally peer reviewed.

Jean Pierre Bikorimana

University of Montreal - Department of Microbiology, Infectious Diseases and Immunology ( email )

University of Montreal
Montreal, QC

Natasha Salame

Université de Montréal - Department of Biomedical Sciences ( email )

C.P. 6128 succursale Centre-ville
Montreal, Quebec H3C 3J7
Canada

Simon Beaudoin

Defence Therapeutics Inc - Research and Development Branch ( email )

Vancouver
Canada

Mohammad Balood

University of Montreal - Department of Pharmacology and Physiology ( email )

C.P. 6128 succursale Centre-ville
Montreal, Quebec H3C 3J7
Canada

Théo Crosson

University of Montreal - Department of Pharmacology and Physiology ( email )

C.P. 6128 succursale Centre-ville
Montreal, Quebec H3C 3J7
Canada

Sebastien Talbot

University of Montreal - Department of Pharmacology and Physiology ( email )

C.P. 6128 succursale Centre-ville
Montreal, Quebec H3C 3J7
Canada

Raimar Loebenberg

University of Alberta

Edmonton, T6G 2R3
Canada

University of Alberta - Faculty of Pharmacy and Pharmaceutical Sciences

Sebastien Plouffe

Defence Therapeutics Inc - Research and Development Branch ( email )

Vancouver
Canada

Moutih Rafei (Contact Author)

University of Montreal - Department of Pharmacology and Physiology ( email )

C.P. 6128 succursale Centre-ville
Montreal, Quebec H3C 3J7
Canada

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