Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors
Abstract
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 E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE2 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 28, 2022
- Source ID
- 10.1038/s41467-022-29026-9
Entities
People
- Andrea Apolo
- Armine Kasabyan
- Charles J. Rosser
- Dan Theodorescu
- Dolores Di Vizio
- F Nikolos
- Hideki Furuya
- Jane Trepel
- Jlenia Guarnerio
- Kazukuni Hayashi
- Keith Syson Chan
- Mark Ellie Alonzo
- Matthew Galsky
- Qianxing Mo
- Xen Ping Hoi
Organizations
- National Cancer Institute
- National Institute of General Medical Sciences
- United States Department of Defense
- United States Department of Health and Human Services