FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308396215> ?p ?o ?g. }

• W4308396215 abstract "<h3>Background</h3> Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) highly expressed on regulatory T-cells (Tregs) inhibit the activation of pro-inflammatory T-cells responsible for eliminating cancer cells. Anti-CTLA-4 can enhance T-cell activation by increasing CD28 co-stimulatory signaling through CTLA-4 blockade or depletion of Tregs by Fc-dependent effector mechanisms. Strategies to improve its therapeutic efficacy are needed as patient response rates to anti-CTLA-4 are low. Response to anti-CTLA-4 has been positively correlated with tumor mutation burden (TMB). Defects in the DNA mismatch repair (MMR) pathway can increase TMB and the production of neoantigens that promote anti-tumor immune responses. Here we investigate the underlying mechanism(s) to which induced MMR deficiency in an immunologically-cold and low TMB tumor model can enhance the therapeutic effect of anti-CTLA-4. We hypothesize that induced MMR deficiency in tumors enhances anti-CTLA-4-mediated Treg depletion and increases the infiltration and activation of effector T-cells. <h3>Methods</h3> MMR deficiency was induced in a syngeneic murine neuro-2a neuroblastoma cell line by knocking-out <i>MLH1</i> expression using CRISPR-Cas9. Wildtype MMR-proficient (pMMR) or induced MMR-deficient (idMMR) neuro-2a cells were inoculated into immunocompetent A/J mice and treated with anti-CTLA-4. Tumors were immunophenotyped by flow cytometry and mixed-lymphocyte reaction assays were used to examine the effects of MMR deficiency and anti-CTLA-4 on T-cell activation and proliferation. <h3>Results</h3> Induced MMR deficiency in neuroblastoma tumors enhances the anti-tumor immune response induced by anti-CTLA-4. MMR deficiency in neuroblastoma tumors promoted anti-CTLA-4-mediated Treg depletion and increased intratumoral CD3⁺ T-cells. idMMR neuroblastoma tumors had an increase of ICOS⁺ T-cells compared to pMMR tumors. In addition, ICOS⁺ T-cells were increased further with anti-CTLA-4 treatment. <h3>Conclusions</h3> Our data show that inducing MMR deficiency in low TMB and immune-cold neuroblastoma tumors can enhance the anti-tumor effect of anti-CTLA-4 by increasing T-cell activation and depletion of Tregs. By understanding the underlying mechanism(s) of anti-CTLA-4 in idMMR tumors, it may justify targeting the MMR pathway to improve the response to immune checkpoint inhibitors in patients with immunologically-cold and/or low TMB tumors that are refractory to immunotherapy. Future studies will assess how inducing MMR deficiency alters the tumor microenvironment to enable anti-CTLA-4-mediated Treg depletion and the significance of ICOS⁺ T-cells in the efficacy of anti-CTLA-4 therapy in this setting." @default.
• W4308396215 created "2022-11-11" @default.
• W4308396215 creator A5006306403 @default.
• W4308396215 creator A5011809763 @default.
• W4308396215 creator A5079903325 @default.
• W4308396215 date "2022-11-01" @default.
• W4308396215 modified "2023-09-26" @default.
• W4308396215 title "464 Anti-CTLA-4 therapy depletes Tregs and expands ICOS⁺T-cells in neuroblastoma tumors with induced DNA mismatch repair deficiency" @default.
• W4308396215 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0464" @default.
• W4308396215 hasPublicationYear "2022" @default.
• W4308396215 type Work @default.
• W4308396215 citedByCount "0" @default.
• W4308396215 crossrefType "proceedings-article" @default.
• W4308396215 hasAuthorship W4308396215A5006306403 @default.
• W4308396215 hasAuthorship W4308396215A5011809763 @default.
• W4308396215 hasAuthorship W4308396215A5079903325 @default.
• W4308396215 hasBestOaLocation W43083962151 @default.
• W4308396215 hasConcept C154317977 @default.
• W4308396215 hasConcept C202751555 @default.
• W4308396215 hasConcept C203014093 @default.
• W4308396215 hasConcept C21705690 @default.
• W4308396215 hasConcept C2776090121 @default.
• W4308396215 hasConcept C2776715637 @default.
• W4308396215 hasConcept C502942594 @default.
• W4308396215 hasConcept C51785407 @default.
• W4308396215 hasConcept C54355233 @default.
• W4308396215 hasConcept C81885089 @default.
• W4308396215 hasConcept C86803240 @default.
• W4308396215 hasConcept C8891405 @default.
• W4308396215 hasConceptScore W4308396215C154317977 @default.
• W4308396215 hasConceptScore W4308396215C202751555 @default.
• W4308396215 hasConceptScore W4308396215C203014093 @default.
• W4308396215 hasConceptScore W4308396215C21705690 @default.
• W4308396215 hasConceptScore W4308396215C2776090121 @default.
• W4308396215 hasConceptScore W4308396215C2776715637 @default.
• W4308396215 hasConceptScore W4308396215C502942594 @default.
• W4308396215 hasConceptScore W4308396215C51785407 @default.
• W4308396215 hasConceptScore W4308396215C54355233 @default.
• W4308396215 hasConceptScore W4308396215C81885089 @default.
• W4308396215 hasConceptScore W4308396215C86803240 @default.
• W4308396215 hasConceptScore W4308396215C8891405 @default.
• W4308396215 hasLocation W43083962151 @default.
• W4308396215 hasOpenAccess W4308396215 @default.
• W4308396215 hasPrimaryLocation W43083962151 @default.
• W4308396215 hasRelatedWork W173798967 @default.
• W4308396215 hasRelatedWork W2015747966 @default.
• W4308396215 hasRelatedWork W2066251089 @default.
• W4308396215 hasRelatedWork W2140516087 @default.
• W4308396215 hasRelatedWork W2411456541 @default.
• W4308396215 hasRelatedWork W2415059733 @default.
• W4308396215 hasRelatedWork W2509717993 @default.
• W4308396215 hasRelatedWork W2620474830 @default.
• W4308396215 hasRelatedWork W2988827179 @default.
• W4308396215 hasRelatedWork W2772898050 @default.
• W4308396215 isParatext "false" @default.
• W4308396215 isRetracted "false" @default.
• W4308396215 workType "article" @default.