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Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody

ABSTRACT: Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody

PROVIDER: PRJNA814218 | ENA |

REPOSITORIES: ENA

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Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody: Bulk TCR sequencing

Project description:The repertoire of tumor-infiltrating T cells is a novel perspective to characterize effective anti-tumor T cell responses. Previous studies reported that the oligoclonal expansion in tumor T-cell repertoire is associated with anti-tumor effects. However, the contribution of the expansion of diverse T-cell clones remained unclear. We demonstrated that the polyclonal fraction of tumor-reactive T-cell repertoire consisting of relatively minor clones, increased in tumor-bearing mice treated with anti-PD-L1 or anti-CD4 monoclonal antibodies (mAbs), while the oligoclonal fraction consisting of major clones was unchanged. Moreover, the polyclonal fraction was enriched with progenitor exhausted T cells, essential for a durable anti-tumor response, and more dependent on CCR7+ migratory dendritic cells, responsible for priming tumor-reactive T cells in the tumor-draining lymph node (dLN). These results proposed that the expansion of diverse tumor-reactive clones, “clonal spreading,” is an important mechanism by which anti-PD-L1 and anti-CD4 treatments exert robust and durable anti-tumor T-cell responses.

2023-05-11 | GSE216795 | GEO

Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody: Bulk TCR sequencing

Project description:Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody: Bulk TCR sequencing

| PRJNA895410 | ENA

Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-11 | GSE198211 | GEO

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

Project description:Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrate that delivery of class I histone deacetylase inhibitor, MS-275, promotes sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We find that MS-275 alters the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ dendritic cells and depletion of regulatory T cells. Activated endogenous CD8+ T cell responses against non-target tumor antigens was critically required for the prevention of tumor recurrence. Importantly, MS-275 alters the immunodominance hierarchy by directing epitope spreading towards endogenous retroviral tumor-associated antigen, p15E. Our data suggest that MS-275 multi-mechanistically improves epitope spreading to promote long-term clearance of solid tumors.

2021-07-03 | GSE179337 | GEO

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

Project description:HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

| PRJNA743304 | ENA

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

Project description:CD137 (4-1BB) is a member of the TNFR family that mediates potent T-cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies. CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137-signaling complex. Moreover, cIAPs are required for CD137 signaling towards the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC-mimetics that trigger cIAPs degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models and cIAPs are also required for signaling from CARs encompassing CD137’s cytoplasmic tail.

2024-05-24 | PXD042585 | Pride

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models

Project description:Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models

| PRJNA914209 | ENA

Profiling of spreading- coupled protein tyrosine phosphorylation

Project description:Protein tyrosine phosphorylation is an important mechanism that regulates cytoskeleton reorganization and cell spreading of migratory cells. A number of cytoskeletal proteins are known to be tyrosine phosphorylated (pY) in different cellular processes. However, the profile of pY proteins during different stages of cell spreading has not been available.

2016-09-28 | PXD004340 | Pride

Leo1 is a Global Regulator of Heterochromatin Cis-spreading

Project description:Domains of heterochromatin play important roles in the maintenance and regulation of eukaryotic genomes. However, the repressive nature of heterochromatin combined with its propensity to self-propagate necessitates the existence of robust mechanisms that limit heterochromatin spreading and thereby avoid silencing of expressed genes. A number of specific sequence elements have been found to serve as barriers to heterochromatin spreading; however, the mechanisms by which spreading is curtailed are generally not well understood. Here we uncover a role for PAF complex component Leo1 in regulating heterochromatin cis-spreading. A genetic screen revealed that loss of Leo1 results in spreading of heterochromatin across a centromeric (IRC) boundary element in fission yeast. Similar heterochromatin spreading was seen upon deletion of other components of the PAF complex, but not other factors involved in transcription-coupled chromatin modification, indicating a specific role for the PAF complex in heterochromatin regulation. Loss of Leo1 is associated with reduced levels of H4K16 acetylation at the boundary, while tethering of the H4K16 acetyltransferase Mst1 to boundary chromatin suppresses heterochromatin spreading in leo1? cells, suggesting that Leo1 antagonises heterochromatin spreading by facilitating H4K16 acetylation. Interestingly, Leo1 also regulates heterochromatin spreading independently of boundaries, and loss of Leo1 causes redistribution of heterochromatin, in particular resulting in substantial expansion of telomeric heterochromatin domains. The PAF complex is known to be an important regulator of transcription-related chromatin modifications; our findings reveal a previously undescribed role for this complex in global regulation of heterochromatin spreading in cis. 8 samples: input (whole cell extract) and IP from H3K9me2 ChIP in wild-type and leo1? cells, in duplicate

2015-05-22 | E-GEOD-61688 | biostudies-arrayexpress

Proteomic characterization of Withaferin A-targeted protein networks for the treatment of monoclonal myeloma gammopathies

Project description:Withaferin A (WA), a natural steroid lactone from the plant Withania Somnifera, has been used for many years in traditional Ayurveda medicine to treat inflammation-related conditions, such as ulcers and rheumatism. Today, WA is most often studied because of its antitumor properties. Although many in vitro and in vivo studies have been performed, the identification of Withaferin A protein targets and of its mechanism of antitumor action remains incomplete. Here, we used quantitative chemoproteomics and differential protein expression analysis to characterize the WA antitumor effects on a multiple myeloma cell model. Identified relevant targets were further validated by Ingenuity Pathway Analysis (IPA) and Western Blot. Canonical pathway analysis revealed targeting of the ubiquitination pathway as a main strategy for WA-induced cell death. Further data suggested that WA targets protein networks that are specific for monoclonal gammopathy of undetermined significance (MGUS) and other closely related disorders, such as multiple myeloma (MM) and Waldenström macroglobulinemia (WM). Moreover, 16 of 20 proteins influenced by WA potentially counteract disease progression, suggesting WA can be used as an effective treatment for MGUS and other closely related disorders.

2018-02-23 | PXD006528 | Pride

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