Abstract B007: Upregulation of PD-L1 as a mechanism of resistance to CD47 inhibition in non-small cell lung cancer
Notice bibliographique
Résumé
Abstract Introduction: Evasion of the immune system is a hallmark of cancer and understanding immune escape mechanisms has led to the development of immunotherapies to boost anti-tumor immunity. CD47 is an immunosuppressive protein that transduces a “don’t eat me” signal when bound to the SIRPα receptor on antigen presenting cells (APCs). Cancer cells exploit CD47 to block phagocytosis by APCs and dampen anti-tumor immune responses. Various inhibitors of the CD47-SIRPα signaling axis, including monoclonal antibodies, have been developed as immunotherapeutic agents for administering CD47 blockade in cancer patients, and are currently being evaluated in clinical trials. Understanding mechanisms of tumor resistance to CD47-targeted immunotherapy will guide its clinical development and could inform rational combination therapies to enhance its efficacy. Since CD47 is prognostically and functionally relevant in non-small cell lung cancer (NSCLC), we investigated the response of two syngeneic, murine lung cancer models to CD47 loss-of-function (LOF). Methods: CRISPR/Cas9 was used to knockout (KO) CD47 in two murine (LLC, CMT167) syngeneic models of NSCLC. Tumor growth studies were conducted in immune competent (C57BL/6) mice orthotopically implanted with wildtype (WT) or CD47 KO cells. Immunophenotyping of tumors was done prior to humane endpoints using flow cytometry to compare immune cell infiltration in WT versus CD47 KO tumors to assess lung tumor response to CD47 LOF. Results: Survival analyses of immunocompetent hosts with orthotopic LLC and CMT tumors revealed that mice with CD47 KO tumors lived longer than those with WT tumors, although CD47 KO tumors were ultimately lethal. Tumor immunophenotyping revealed higher frequencies of MHC-IIhighCD80+ M1 macrophages and activated cytotoxic CD69+CD8+ T cells in CD47 KO tumors compared to WT. Moreover, the percentage of PD-L1+ tumor and myeloid cells was greater in CD47 KO tumors compared to WT tumors, suggesting PD-L1 may be upregulated on various cell types in the TME as a compensation mechanism when CD47 is inhibited. Conclusion: Consistent with the literature, our findings show that CD47 LOF in lung cancer cells prolongs the survival of tumor-bearing mice and promotes infiltration of anti-tumor immune cells in two orthotopic, syngeneic NSCLC models. Upregulation of PD-L1 in cancer and myeloid cells from CD47 KO tumors was also observed, revealing a putative PD-L1-driven mechanism of resistance to CD47 blockade. Although additional preclinical and clinical studies are needed to confirm the generalizability of our observations and to validate them in patients treated with CD47-targeted therapy, our findings provide evidence to support continued development of approaches for combining CD47 and PD-L1 blockade as an effective immunotherapeutic strategy for the treatment of NSCLC. Citation Format: Asa P.Y Lau, Kelsie L Thu. Upregulation of PD-L1 as a mechanism of resistance to CD47 inhibition in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B007.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».