Biology subjects

Apcher, S.

Publications and source records attributed to Apcher, S..

4 recordsLinked to original sources

bioRxiv2025

Decoy Antibodies Block Extracellular HSP70, Prevent Self Signaling and Inhibit Melanoma Cell Survival

Melanoma cells actively secrete melanosomes-large, extracellular vesicles (EVs) enriched with oncogenic factors that reprogram the tumor microenvironment, enhance self-signaling, and promote tumor growth. Despite their abundance and immunogenic potential, humoral responses to melanoma-derived melanosomes remain unexplored. Here, we identify a novel immune surveillance mechanism in which melanosome-elicited decoy antibodies target melanoma-derived melanosomes by binding to the extracellular form of heat shock protein 70 (HSP70), a chaperone broadly implicated in cancer cell survival and stress adaptation. Anti-HSP70 decoy antibodies potently and effector-independently inhibit growth and survival of both murine and human melanoma cells and suppress key transcriptional programs involved in proliferation, cytoskeletal dynamics, and metabolism. In a preclinical B16 melanoma model, prophylactic administration of decoy monoclonal antibodies Mel322-34 and Mel321-35 conferred significant survival benefits of 27% and 48%, respectively. Strikingly, anti-HSP70 antibodies were enriched in the sera of melanoma patients achieving complete responses to immune checkpoint blockade, in contrast to non-responders with progressive disease. Collectively, our findings uncover a novel EV-antibody axis as a promising avenue to block cancer-promoting signaling pathways. Decoy autoantibodies targeting the extracellular form of HSP70 advance the understanding of tumor-intrinsic vulnerability and promote biomarker-driven immunotherapy in melanoma.

immunology↗

bioRxiv2019

Tumors escape immunosurveillance by overexpressing the proteasome activator REGγ

The success of CD8+ T cell based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during the pioneer round of mRNA translation (pioneer translation products, or PTPs) can be a potentially important source of tumor specific peptides, given the presence of aberrant splicing and transcription associated with oncogenesis. Here we show that cancer cells up-regulation of the REG{gamma} proteasome regulator results in increased destruction of PTP-derived peptides in the nucleus thus subverting immunosurveillance. These findings add to understanding of the role of REG{gamma} in antigen processing and identify it as a druggable target for improving the efficacy of cancer immunotherapy.\n\nSignificanceWith the clear success of CD8+ T cell based immunotherapy, it is critical to understand i) how tumor cells generate MHC-I peptide antigens? and ii) the various mechanisms used by cancer cells to evade immunosurveillance. One of them is to up-regulate the REG{gamma} proteasome regulator which results in an increase destruction of MHC-I peptides in the nucleus thus subverting immunosurveillance.

immunology↗

bioRxiv2019

Splicing inhibition enhances the antitumor immune response through increased tumor antigen presentation and altered MHC-I immunopeptidome

The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented by tumor cells on MHC class I molecules. Alternative translation events emerged as a rich source of TAs and generate the so-called Pioneer Translation Products (PTPs), which are peptides generated from unspliced mRNA. We demonstrated in vitro and in vivo that the splicing inhibitor isoginkgetin and a derived water-soluble and less toxic molecule, IP2, act at the production stage of the PTPs. We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and decreases tumor growth in vivo in an immune-dependent manner. Furthermore, IP2 treatment induces a long-lasting antitumor response. Finally, we observed that the epitope repertoire displayed on MHC-I molecules is altered upon treatment with IP2 with the modulation of pre-existing peptides and the emergence of novel antigens derived from both coding and allegedly non-coding sequences.\n\nSignificanceIP2 is a new efficient \"first in class\" immunomodulator of the MHC I presentation pathway. IP2 reduces the growth of sarcoma MCA205 and melanoma B16F10 tumors bearing the PTP-derived SL8 epitope and significantly extends mice survival. IP2 treatment reshape the cancer cell MHC-I immunopeptidome. These findings add to the understanding of the role of the splicing machinery in antigen production and presentation and identify the spliceosome as a druggable target to enhance cancer immunosurveillance.

immunology↗

bioRxiv2019

Fanconi anemia proteins are required to maintain nucleolar homeostasis.

The majority of inherited bone marrow failure (iBMF) syndromes are associated to nucleolar and/or ribosomal abnormalities, but Fanconi anemia (FA), the most common iBMF, is attributed to alterations in DNA damage responses. However, the involvement, if any, of the FA (FANC) proteins in the maintenance of nucleolar functions and/or ribosome biogenesis is yet unexplored. Here, we report that FANC pathway loss-of-function is associated to a loss of the nucleolar homeostasis, demonstrating increased rDNA rearrangements, accumulation of nucleolar DNA damage, nucleolar protein mislocalization, and a p53-independent induction of the growth inhibitory protein p21. Moreover, specifically associated to FANCA loss-of-function, which is responsible for approximately 65% of FA cases, we observed reduced rDNA transcription and rRNA processing as well as alteration in protein synthesis and polysome profiles. Thus, we have identified nucleolar consequences associated with FANC pathway deficiency, challenging current hypothesis on the physiopathology of FA.

cell biology↗