bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.06.14.545005

Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer

Sharma, P.·Zhang, X.·Ly, K.·Kim, J. H.·Wan, Q.·Kim, J.·Lou, M.·Kain, L.·Teyton, L.·Winau, F.
View original source ↗Export metadata ↓

Abstract

Tumors develop strategies to evade immunity by suppressing antigen presentation. Here, we show that prosaposin drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor DCs leads to cancer immune escape. We found that lysosomal prosaposin and its single saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, TGF-{beta} induced hyperglycosylation of prosaposin and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. In melanoma patients, we found similar prosaposin hyperglycosylation in tumor-associated DCs, and reconstitution with prosaposin rescued activation of tumor-infiltrating T cells. Targeting tumor DCs with recombinant prosaposin triggered cancer protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of prosaposin in tumor immunity and escape and introduce a novel principle of prosaposin-based cancer immunotherapy. One Sentence SummaryProsaposin facilitates antigen cross-presentation and tumor immunity and its hyperglycosylation leads to immune evasion.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Sharma, P., Zhang, X., Ly, K., Kim, J. H., Wan, Q., Kim, J., Lou, M., Kain, L., Teyton, L., Winau, F.. 2023-06-14. Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer. https://doi.org/10.1101/2023.06.14.545005

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and Gag-specific T cells

Despite decades of HIV-1 vaccine development, the clonal and cellular determinants of durable vaccine-induced T cell memory remain incompletely understood. Here, we combined antigen-specific T cell receptor (TCR) identification, longitudinal TCR sequencing, and single-cell multi-omics to characterize Env- and Gag-specific memory precursor T cells elicited by the HIV Vaccine Trials Network (HVTN) 505 DNA prime-recombinant adenovirus serotype 5 (rAd5) boost (DNA/rAd5) vaccine regimen. We developed a generalizable high-throughput approach to identify HIV-1 Env- and Gag-specific TCRs and found distinct patterns of clonal expansion, persistence, and contribution to memory between Env- and Gag-specific CD8 T cell responses. The DNA prime and rAd5 boost differentially shaped these repertoires, with rAd5-induced clones contributing proportionally more to the Gag-specific than to the Env-specific memory precursor compartment. Single-cell immune profiling further revealed distinct memory precursor states, with Env-specific responses enriched for GZMBPRF1 cytotoxic effector-memory (EM) CD8 T cells and Gag-specific responses containing a larger cycling/proliferative population. Together, these findings demonstrate that heterologous DNA/rAd5 vaccination generates antigen-specific CD8 T cell memory with distinct clonal trajectories and cellular programs, providing new insights into how vaccine platform and antigen-specificity shape the durability and functional properties of HIV-1 specific cellular immunity.

immunology↗
bioRxiv2026

MicroRNA-146a Deficiency Protects NOD Mice from Autoimmune Diabetes by Enhancing c-Rel-Dependent Regulatory T Cell Function

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T-cell mediated destruction of pancreatic islet {beta}-cells with genetic, environmental, and molecular triggers involved in disease pathogenesis. Patients with T1D have elevated serum levels of microRNA146a (miR146a). Polymorphisms in the miR146a gene that result in reduced expression of miR146a are associated with protection from T1D. We studied physiological regulators of miR146a expression and found that both hyperglycemia and elevated O-GlcNAcylation increased miR146a expression in T cells. Peripheral blood mononuclear cells (PBMCs) from T1D patients showed increased miR146a and O-GlcNAc transferase (OGT) expression, suggesting increased O-GlcNAcylation may promote miR146a expression in T1D patients. To determine the genetic and developmental role of miR146a in T1D, we generated miR146a-knockout (KO) non-obese diabetic (NOD) mice and found that absence of miR146a significantly protected NOD mice from spontaneous autoimmune diabetes. While we found no impact of miR146a knockout on general hematopoietic parameters and immune cell populations, remarkably, immune cell infiltration into the pancreas was significantly attenuated. Protection from autoimmune diabetes in miR146a-KO NOD mice was associated with increased regulatory T (Treg) cells in the spleen and pancreatic lymph node. Mechanistically, absence of miR146a increased NF-{kappa}B c-Rel expression in Treg cells and enhanced c-Rel binding at the Forkhead box protein P3 (FOXP3) promoter, which positively regulated Treg cell development and suppressor function, offering protection from T1D in miR146a-KO NOD mice. Our findings reveal miR146a as a key regulator of Treg cell-mediated immune tolerance through controlling NF-{kappa}B c-Rel-dependent FOXP3 expression and suggest targeting miR146a as a potential strategy to restore peripheral tolerance in T1D.

immunology↗
bioRxiv2026

Patient-Derived Melanoma Organoids Preserve Tumor-Immune Heterogeneity and Reveal Context-Dependent Responses to Immune Checkpoint Blockade

Abstract Background: Experimental models that retain endogenous tumor immune complexity are needed to investigate heterogeneous responses to immune checkpoint inhibitors (ICIs) in melanoma. We established patient-derived melanoma organoids (PDMOs) to examine retention of parental tumor cellular components and investigate patient-specific and context-dependent responses to checkpoint blockade. Methods: Fresh melanoma specimens (n=50), including primary tumors, neoadjuvant-treated tumors and tumor-infiltrating lymphocyte (TIL) associated samples were processed for Matrigel-embedded culture of patient-derived melanoma organoids (PDMOs). Characterization and functional studies were performed in subsets of established cultures. Immunofluorescence assessed tumor, stromal, immune, and checkpoint-marker expression in PDMOs and matched parental tissues. NGFR expression was evaluated in relation to organoid establishment and growth. Responses to anti PD1 alone or combined with anti-LAG3 or anti-CTLA4 therapies were evaluated using viability and morphological analyses, with selected models undergoing immune phenotyping and multiplex cytokine profiling. Available clinical outcomes were used for exploratory comparison. PDMOs and matched two-dimensional cultures were evaluated under 21% and 5% oxygen conditions. Results: PDMOs were established from 30 of 50 specimens (60%) and retained melanoma, stromal, lymphoid, and myeloid components identified in matched parental tissues during early culture, together with immune checkpoint expression. Higher NGFR (CD271) expression was associated with greater organoid-forming capacity in an exploratory subset. Responses to checkpoint blockade varied across patient-derived models and regimens, with combination blockade not uniformly producing lower viability than PD1 monotherapy. Ex vivo responses showed parallels with available clinical outcomes, with discordant cases also observed. In three selected PDMOs, divergent PD-1 responses were accompanied by differences in T-cell and myeloid representation, MHCII and AXL expression, and inflammatory versus immunoregulatory cytokine profiles. Under normoxic conditions, PDMOs and matched two-dimensional cultures exhibited divergent treatment sensitivities, including clinically responding cases in which sensitivity was retained in PDMOs but attenuated in monolayers. Changing oxygen tension further altered checkpoint sensitivity within individual PDMOs, with the direction and magnitude of the observed shifts varying by model and regimen. Conclusions: Early passage PDMOs retain key endogenous tumor, immune, and stromal components and support functional investigation of patient-derived melanoma biology. Their heterogenous responses across checkpoint regimens and oxygen conditions provide a platform for investigating how tumor-immune composition and environmental context influence treatment sensitivity.

immunology↗