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T cells expressing modified Fc receptor infiltrate solid tumors and provide long-term anti-tumor protection

ABSTRACT: T cells expressing modified Fc receptor infiltrate solid tumors and provide long-term anti-tumor protection

PROVIDER: PRJNA1096041 | ENA |

REPOSITORIES: ENA

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T cells expressing modified Fc receptor infiltrate solid tumors and provide long-term anti-tumor protection

Project description:The clinical success of T cells armed with chimeric antigen receptor (CAR-T) to cure patients with hematological malignancies, has demonstrated the immense therapeutic potential of equipping T cells with synthetic receptors. Nonetheless, the scarcity of tumor-specific antigens and the limited capacity of T cells to infiltrate the tumor microenvironment significantly limit its clinical use in solid tumors. Here, we provide evidence of FcγRI expressing CD8+ T cells presence in both mouse and human tumors as well as inflammation sites. Inspired by this discovery, we engineered a novel FcγRI-based receptor for T cells. This design allows T cells to target tumor cells indirectly through antibody intermediates, separating the processes of antigen recognition and T cell activation. This approach allows T cells to initiate killing exclusively against cells with antigen overexpression, thus minimizing on-target off-tumor cytotoxicity. Interestingly, the modified FcγRI expression in T cells unexpectedly induces constitutive expression of the CD11b integrin. This additional effect enables the engineered T cells to efficiently infiltrate the tumor basement membrane and develop an effector memory phenotype, potentially promoting long-term anti-tumor activity. The presence of these effector memory subsets characterized complete responders and mediated tumor regression upon rechallenge. Overall, T cell-mediated ADCC suggests an alternative, novel strategy for conventional CAR-T cell design, enables T cells to differentiate between target cells expressing the same antigen, and overcomes the physical barriers of the tumor microenvironment.

2024-12-01 | GSE263177 | GEO

Multivalent S2-subunit Vaccines Provide Broad Protection Against Clade 1 Sarbecoviruses

Project description:The continuing emergence of immune evasive SARS-CoV-2 variants and the previous SARS-CoV-1 outbreak have accentuated the need for broadly protective sarbecovirus vaccines. Targeting the conserved S2-subunit of SARS-CoV-2 is a particularly promising approach to elicit broad protection. Here, expanding on our previous work with S2-based vaccines, we developed a nanoparticle vaccine displaying multiple copies of the SARS-CoV-1 S2 subunit. This vaccine alone, or as a cocktail with a SARS-CoV-2 S2 subunit vaccine, protected female transgenic K18-hACE2 mice from challenges with Omicron subvariant XBB as well as several sarbecoviruses identified as having pandemic potential including the bat sarbecovirus WIV1, BANAL-236, and a pangolin sarbecovirus. Challenge studies in female Fc- receptor knockout mice revealed that antibody-based cellular effector mechanisms played a role in protection elicited by these vaccines. These results demonstrate that our S2-based vaccines provide broad protection against clade 1 sarbecoviruses and offer insight into the mechanistic basis for protection.

2024-11-21 | GSE282247 | GEO

Multivalent S2-subunit Vaccines Provide Broad Protection Against Clade 1 Sarbecoviruses

Project description:Multivalent S2-subunit Vaccines Provide Broad Protection Against Clade 1 Sarbecoviruses

| PRJNA1187638 | ENA

Geitlerinema sp. FC II strain:FC II

Project description:Geitlerinema sp. FC II strain:FC II Genome sequencing and assembly

| PRJNA399071 | ENA

Immunoprofiling of prostate cancer infiltrate

Project description:Immunoprofiling of prostate cancer infiltrate

| PRJNA644438 | ENA

Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity

Project description:SARS-CoV-2 has spread globally and caused the COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 are in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected mice. Whereas Fc effector functions are fully dispensable when mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact but not LALA-PG loss of Fc effector function variant mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and enhanced tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Our study demonstrates that therapeutic neutralizing mAbs require Fc effector functions to reduce SARS-CoV-2 infection and modulate protective immune responses.

2021-03-01 | GSE161615 | GEO

Mapping of nascent RNA in MLL2 F/F and FC/FC MEF cells

Project description:Global Run-On has been performed in MLL2 F/F and FC/FC MEF cells. The aim of the experiment is to test how the lack of MLL2 affects nascent RNA transcription. Four samples were analyzed - 2 independent replicates. The experiments were performed using immortalized mouse embryonic fibroblasts (MEF) in which both MLL2 alleles were targeted by the loxp system (F/F cells). Tamoxifen treatment of the F/F cells for 24 hours results in the excision of both MLL2 alleles (FC/FC cells).

2016-04-13 | E-GEOD-73126 | biostudies-arrayexpress

Immunoprofiling of mouse prostate cancer infiltrate

Project description:Immunoprofiling of mouse prostate cancer infiltrate

| PRJNA958227 | ENA

IKZF1 as a Master Regulator of Immune Infiltrate Recruitment in Solid Tumors

Project description:IKZF1 as a Master Regulator of Immune Infiltrate Recruitment in Solid Tumors

| PRJNA436150 | ENA

Mapping of nascent RNA in MLL2 F/F and FC/FC MEF cells

Project description:Global Run-On has been performed in MLL2 F/F and FC/FC MEF cells. The aim of the experiment is to test how the lack of MLL2 affects nascent RNA transcription.

2016-04-13 | GSE73126 | GEO

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