Matches in SemOpenAlex for { <https://semopenalex.org/work/W4282923495> ?p ?o ?g. }
Showing items 1 to 90 of
90
with 100 items per page.
- W4282923495 endingPage "3514" @default.
- W4282923495 startingPage "3514" @default.
- W4282923495 abstract "Abstract A primary mechanism of cancer immunotherapy resistance involves downregulation of specific antigens or major histocompatibility complex (MHC) based antigen presentation, which renders tumor cells invisible to αβ T cells, but not γδ T cells. Recently, a two-step model of γδ T cell activation has emerged, wherein one butyrophilin (BTN, i.e., BTN2A1) directly binds the γδ TCR but is only activated if certain molecular patterns (e.g., phosphoantigens) facilitate recruitment of a second BTN (i.e., BTN3A1) into a complex to form a BTN2A1/3A1 heterodimer. The BTN2A1/3A1 complex specifically activates the Vγ9Vδ2 T cells found in the peripheral blood in response to phosphoantigen build up in tumor cells. The unique mechanism of action and specificity of γδ TCR/BTN interactions suggests that therapeutic proteins comprising specific BTN heterodimers could be used to target specific γδ T cell populations to tumor cells which lack expression of high affinity neoantigens or MHC class I molecules. In this study, we generated bispecific γδ T cell engagers (GADLEN) containing heterodimeric BTN2A1 and BTN3A1 extracellular domains (ECD) fused via inert Fc linkers to scFv domains targeting a tumor-antigen (CD19 or CD33) to test their ability to modulate Vγ9Vδ2 T cells and to promote tumor cell killing in co-culture assays. GADLEN induced proliferation, degranulation and cytokine production including IFNγ and TNFα in Vγ9Vδ2 T cells but requires co-stimulation of a natural cytotoxicity receptor (via anti-NKG2D) or T-cell co-stimulatory receptor (via anti-CD28), highlighting the parallels of signal 1 and signal 2 requirements of TCR activation in αβ- and γδ- T cells. In Vγ9Vδ2 T cells and tumor co-culture assays, the addition of GADLEN alone enhanced killing of CD19+ lymphoma cells such as Daudi and Raji, expressing known ligands for CD28 (e.g., CD80 and CD86). Similarly, GADLEN enhanced Vγ9Vδ2 T cell-mediated killing of K562 cells engineered to express CD19, which express MICA/B (ligands for NKG2D) on the cell surface. In addition, the CD33-targeted GADLEN alone was able to specifically kill acute myeloid leukemia cells expressing CD33 and costimulatory ligands (e.g., CD80 and CD86) in a mechanism similar to the CD19-targeted GADLEN construct. These results highlight the ability of GADLENs in promoting targeted killing of tumor cells by providing the “active” heterodimeric BTN2A1 and BTN3A1 that is critical to enhance cytotoxic killing by Vγ9Vδ2 T cells. Furthermore, this study provides mechanistic insights into BTN-mediated activation of Vγ9Vδ2 T cells and offers proof of concept for using antigen-targeted butyrophilin heterodimeric fusion proteins for the treatment of cancer. Citation Format: Anne Lai, Arpita Patel, Faraha Brewer, Kinsley Evans, Kellsey Johannes, Louis Gonzalez, Kyung Jin Yoo, George Fromm, Keith Wilson, Taylor H. Schreiber, Suresh de Silva. Bispecific gamma delta T cell engagers containing butyrophilin 2A1/3A1 heterodimeric fusion protein efficiently activate Vg9Vd2 T cells and promote tumor cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3514." @default.
- W4282923495 created "2022-06-16" @default.
- W4282923495 creator A5001670202 @default.
- W4282923495 creator A5004436831 @default.
- W4282923495 creator A5016340598 @default.
- W4282923495 creator A5026441848 @default.
- W4282923495 creator A5026833986 @default.
- W4282923495 creator A5033794726 @default.
- W4282923495 creator A5034258250 @default.
- W4282923495 creator A5041541957 @default.
- W4282923495 creator A5063908914 @default.
- W4282923495 creator A5065243123 @default.
- W4282923495 creator A5087439323 @default.
- W4282923495 date "2022-06-15" @default.
- W4282923495 modified "2023-10-07" @default.
- W4282923495 title "Abstract 3514: Bispecific gamma delta T cell engagers containing butyrophilin 2A1/3A1 heterodimeric fusion protein efficiently activate Vg9Vd2 T cells and promote tumor cell killing" @default.
- W4282923495 doi "https://doi.org/10.1158/1538-7445.am2022-3514" @default.
- W4282923495 hasPublicationYear "2022" @default.
- W4282923495 type Work @default.
- W4282923495 citedByCount "0" @default.
- W4282923495 crossrefType "journal-article" @default.
- W4282923495 hasAuthorship W4282923495A5001670202 @default.
- W4282923495 hasAuthorship W4282923495A5004436831 @default.
- W4282923495 hasAuthorship W4282923495A5016340598 @default.
- W4282923495 hasAuthorship W4282923495A5026441848 @default.
- W4282923495 hasAuthorship W4282923495A5026833986 @default.
- W4282923495 hasAuthorship W4282923495A5033794726 @default.
- W4282923495 hasAuthorship W4282923495A5034258250 @default.
- W4282923495 hasAuthorship W4282923495A5041541957 @default.
- W4282923495 hasAuthorship W4282923495A5063908914 @default.
- W4282923495 hasAuthorship W4282923495A5065243123 @default.
- W4282923495 hasAuthorship W4282923495A5087439323 @default.
- W4282923495 hasConcept C147483822 @default.
- W4282923495 hasConcept C148125776 @default.
- W4282923495 hasConcept C153911025 @default.
- W4282923495 hasConcept C154317977 @default.
- W4282923495 hasConcept C167672396 @default.
- W4282923495 hasConcept C185592680 @default.
- W4282923495 hasConcept C19317047 @default.
- W4282923495 hasConcept C202751555 @default.
- W4282923495 hasConcept C203014093 @default.
- W4282923495 hasConcept C207936829 @default.
- W4282923495 hasConcept C2776090121 @default.
- W4282923495 hasConcept C2777701055 @default.
- W4282923495 hasConcept C2780674031 @default.
- W4282923495 hasConcept C3875195 @default.
- W4282923495 hasConcept C55493867 @default.
- W4282923495 hasConcept C86803240 @default.
- W4282923495 hasConcept C8840205 @default.
- W4282923495 hasConcept C8891405 @default.
- W4282923495 hasConcept C95444343 @default.
- W4282923495 hasConceptScore W4282923495C147483822 @default.
- W4282923495 hasConceptScore W4282923495C148125776 @default.
- W4282923495 hasConceptScore W4282923495C153911025 @default.
- W4282923495 hasConceptScore W4282923495C154317977 @default.
- W4282923495 hasConceptScore W4282923495C167672396 @default.
- W4282923495 hasConceptScore W4282923495C185592680 @default.
- W4282923495 hasConceptScore W4282923495C19317047 @default.
- W4282923495 hasConceptScore W4282923495C202751555 @default.
- W4282923495 hasConceptScore W4282923495C203014093 @default.
- W4282923495 hasConceptScore W4282923495C207936829 @default.
- W4282923495 hasConceptScore W4282923495C2776090121 @default.
- W4282923495 hasConceptScore W4282923495C2777701055 @default.
- W4282923495 hasConceptScore W4282923495C2780674031 @default.
- W4282923495 hasConceptScore W4282923495C3875195 @default.
- W4282923495 hasConceptScore W4282923495C55493867 @default.
- W4282923495 hasConceptScore W4282923495C86803240 @default.
- W4282923495 hasConceptScore W4282923495C8840205 @default.
- W4282923495 hasConceptScore W4282923495C8891405 @default.
- W4282923495 hasConceptScore W4282923495C95444343 @default.
- W4282923495 hasIssue "12_Supplement" @default.
- W4282923495 hasLocation W42829234951 @default.
- W4282923495 hasOpenAccess W4282923495 @default.
- W4282923495 hasPrimaryLocation W42829234951 @default.
- W4282923495 hasRelatedWork W1953155836 @default.
- W4282923495 hasRelatedWork W2028914759 @default.
- W4282923495 hasRelatedWork W2062537693 @default.
- W4282923495 hasRelatedWork W2091567124 @default.
- W4282923495 hasRelatedWork W2157360074 @default.
- W4282923495 hasRelatedWork W2169956921 @default.
- W4282923495 hasRelatedWork W2248619413 @default.
- W4282923495 hasRelatedWork W2500936808 @default.
- W4282923495 hasRelatedWork W3043035828 @default.
- W4282923495 hasRelatedWork W4233410145 @default.
- W4282923495 hasVolume "82" @default.
- W4282923495 isParatext "false" @default.
- W4282923495 isRetracted "false" @default.
- W4282923495 workType "article" @default.