Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S

Background Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function is unknown. Methods In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function. Results Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression. Conclusion These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

The destruction of cosmological minihalos by primordial supernovae

We present numerical simulations of primordial supernovae in cosmological minihalos at z ~ 20. We consider Type II supernovae, hypernovae, and pair instability supernovae (PISN) in halos from 6.9 × 105 to 1.2 × 107 M, those in which Population III stars are expected to form via H2 cooling. Our simulations are the first to follow the evolution of the blast from a free expansion on spatial scales of 10−4 pc until its approach to pressure equilibrium in the relic H II region of the progenitor, ~1000 pc. Supernovae in H II regions first expand adiabatically and then radiate strongly upon collision with baryons ejected from the halo during its photoevaporation by the progenitor. In contrast to previous findings, supernovae in neutral halos promptly emit most of their kinetic energy as X-rays, but retain enough momentum to seriously disrupt the halo. Explosions in H II regions escape into the IGM, but neutral halos confine the blast and its metals. In H II regions, a prompt second generation of stars may form in the remnant at radii of 100-200 pc. Explosions confined by massive halos instead recollapse, with infall rates in excess of 10−2 M yr−1 that heavily contaminate their interior. This fallback may either fuel massive black hole growth at very high redshifts or create the first globular clusters with radii of 10-20 pc at the center of the halo. Our findings suggest that the first primitive galaxies may therefore have formed sooner, with greater numbers of stars and distinct chemical signatures, than in current models

Efficiency and Mechanism of Antigen-specific CD8(+) T-cell Activation Using Synthetic Long Peptides

Personalised Therapeutic

Contemporary management and outcome of myelomeningocele: the Rotterdam experience

Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Identification of novel essential regulators in the MHC class I network

Chemical Immunolog

Neurosurgeons' opinions on the prenatal management of myelomeningocele

Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR

Transplantation and autoimmunit

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

Transplantation and immunomodulatio