Nature communications, 2022-03, Vol.13 (1), p.1487-1487, Article 1487
2022
Details
- Autor(en) / Beteiligte
- Titel
- Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors
- Ist Teil von
- Nature communications, 2022-03, Vol.13 (1), p.1487-1487, Article 1487
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2022
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them "immune-excluded". Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E (PGE ) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This "iDAMP blockade" approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-022-29026-9Titel-ID: cdi_doaj_primary_oai_doaj_org_article_176073b4ee2c4398bc3a707bca588745
- Format
- –
- Schlagworte
- Animal models, Animals, Anticancer properties, Apoptosis, Bladder, Bladder cancer, Cancer, CD8 antigen, CD8-Positive T-Lymphocytes, Cell Death, Chemotherapy, Clinical trials, Cyclooxygenase-2, Damage patterns, Dendritic cells, Granzyme B, Humans, Immune checkpoint inhibitors, Immunogenicity, Immunotherapy, Inflammation, Invasiveness, Lymphocytes, Lymphocytes T, Metastases, Methyl isobutyl carbinol, Mice, Muscles, Patients, PD-1 protein, Platinum, Prostaglandin E2, Prostaglandins E, Tumors, Urinary Bladder Neoplasms - drug therapy, γ-Interferon