Mohsen et al. showed that a low-affinity LCMV p33-derived A4Y peptide linked to a bacteriophage Qβ virus-like particle induced a robust and specific T cell response, but showed limited cross-reactivity to p33 and failed to protect against B16F10p33 tumor growth. Qβ-A4Y combined with Treg-depleting anti-CD25 increased CD8+ T cell infiltration into tumors and migration away from blood vessels. Treg depletion enhanced the antitumor activity of Qβ-A4Y, promoted T cell-mediated tumor-free survival, enhanced T cell cross-reactivity, and increased the effectiveness of a vaccine targeting multiple naturally low-affinity tumor-associated antigens.
Contributed by Shishir Pant
ABSTRACT: TCR repertoires against tumors lack high-affinity TCRs and are further suppressed by Tregs. We hypothesized that Treg depletion enhances the antitumor efficacy of low-affinity T cells. Using the weak agonistic peptide A4Y derived from LCMV glycoprotein peptide p33 as a model antigen and VLPs as a vaccine platform, we tested this approach. In a separate low-affinity model, we targeted B16F10 melanoma with our multi-target vaccine. Results revealed limited in vivo lytic cross-reactivity between A4Y and p33 peptides, and the A4Y-vaccine alone failed to inhibit B16F10p33 tumor progression. However, combining A4Y-vaccine with Treg depletion triggered a robust immune response, characterized by increased CD8+ T cell infiltration, enhanced T cell functionality, and tumor-free survival. Infiltrating T cells also exhibited closer spatial proximity and heightened migration from blood vessels. Similarly, combining low-affinity vaccine with Treg depletion enhanced antitumor responses. These findings highlight the potential of Treg depletion to advance vaccination strategies targeting TAAs with low-affinity T cells.
Author Info: (1) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. mona.mohsen@unibe.ch. Department for BioMedical Research, University of Bern, Ber
Author Info: (1) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. mona.mohsen@unibe.ch. Department for BioMedical Research, University of Bern, Bern, Switzerland. mona.mohsen@unibe.ch. DeepVax GmbH, 8487 Rmismhle, Zrich, Switzerland. mona.mohsen@unibe.ch. (2) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences (GCB), Bern, Switzerland. (3) Department for BioMedical Research, University of Bern, Bern, Switzerland. (4) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. (5) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. (6) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences (GCB), Bern, Switzerland. (7) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences (GCB), Bern, Switzerland. (8) Department for BioMedical Research, University of Bern, Bern, Switzerland. DeepVax GmbH, 8487 Rmismhle, Zrich, Switzerland. Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (9) COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland. (10) Department of Rheumatology and Immunology, Inselspital, University of Bern, Bern, Switzerland. Department for BioMedical Research, University of Bern, Bern, Switzerland. Nuffield Department of Medicine, The Henry Welcome Building for Molecular Physiology, The Jenner Institute, University of Oxford, Oxford, UK.
