Periodic Reporting for period 1 - PhosPepPres (Improving Peptide-Based Anti-Cancer Vaccines with Phosphatase Inhibitors)
Okres sprawozdawczy: 2023-08-01 do 2025-01-31
Peptide-based vaccines hold great potential for immunotherapy by stimulating pathogen- or cancer-specific T cell responses. These vaccines rely on the endocytosis of antigenic peptides by dendritic cells (DCs), followed by intracellular proteolytic processing, epitope loading onto major histocompatibility complex (MHC) class I and II molecules, and subsequent presentation to antigen-specific T cells. Despite promising immunogenicity in preclinical models, peptide-based vaccines have largely failed to demonstrate efficacy in clinical trials. A key limitation is the insufficient presentation of antigenic epitopes on MHC molecules. Enhancing intracellular antigen processing could therefore improve vaccine efficacy. In this project, we evaluated the technical feasibility and translational potential of a novel strategy: co-administration of antigenic peptides with phosphatase inhibitors to enhance cross-presentation. Specifically, we assessed the impact of phsophatase inhibition on antigen cross-presentation by human monocyte-derived macrophages and DCs, using T cell reporter cell lines specific for the tumor-associated antigens NY-ESO-1 and gp100. Our findings indicate that phosphatase inhibition, particularly with the SHP-1/2 inhibitor NSC-87877 significantly reduces the cross-presentation efficiency of both antigens. Mechanistically, we demonstrate that SHP-1/2 inhibition disrupts endo/lysosomal acidification and impairs the activation of cathepsin proteases, which are essential for antigen processing. Consequently, this approach does not enhance cross-presentation and may even limit the effectiveness of combination therapies with immune checkpoint inhibitors. In fact, these results challenge current strategies that combine phosphatase inhibitors with checkpoint blockade, as they could have unintended detrimental effects on tumor immune responses. Given these findings, we explored alternative approaches with potential for patentability and commercialization, including co-encapsulation of kinase inhibitors.
WP1 concerned the technical and scientific aspects and was accomplished as planned. In WP1, we tested phosphatase inhibitors for their ability to enhance activation of helper and cytolytic T cells. As planned, we used human monocyte-derived macrophages and dendritic cells, using T cell reporter cell lines specific for epitopes derived from cancer antigens NY-ESO-1 and gp100. Our findings indicate that phosphatase inhibition significantly reduces the cross-presentation efficiency of both antigens. Mechanistically, we show that SHP-1/2 inhibition by small molecule inhibitor NSC-87877 blocks endo/lysosomal acidification and the activation of cathepsin proteases. This has a two severe consequences: first it does not support our valorisation idea, as co-encapsulation of phosphatase inhibitors will make anti-cancer vaccines less active. However, there might still be some valorisation potential, for example as a therapeutic strategy in conditions where cross-presentation is less desirable (e.g. auto immune disease, allergy), or by pursuing the opposite approach and inhibiting kinases, the counterparts of phosphatases. However, a second severe implication, as the reduction of antigen cross-presentation upon SHP-1/2 inhibition potentially limits the effectiveness of the combination therapy with immune checkpoint inhibition. This potentially has major societal impact, given studies addressing combination therapies with these very same phosphatase inhibitors and immune checkpoint inhibitor therapy. We therefore decided to publish our results showing that SHP1/2 inhibition inhibits antigen cross-presentation in an open access journal, and it is currently under review.
As mentioned above, a second severere implication, as the reduction of antigen cross-presentation upon SHP-1/2 inhibition potentially limits the effectiveness of the combination therapy with immune checkpoint inhibition. This potentially has major societal impact, given studies addressing combination therapies with these very same phosphatase inhibitors and immune checkpoint inhibitor therapy. We therefore decided to publish our results showing that SHP1/2 inhibition inhibits antigen cross-presentation in an open access journal, and it is currently under review.