Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors

Fotis Nikolos, Kazukuni Hayashi, Xen Ping Hoi, Mark Ellie Alonzo, Qianxing Mo, Armine Kasabyan, Hideki Furuya, Jane Trepel, Dolores Vizio, Jlenia Guarnerio, Dan Theodorescu, Charles Rosser, Andrea Apolo, Matthew Galsky and Keith Syson Chan ()
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Fotis Nikolos: Cedars-Sinai Medical Center
Kazukuni Hayashi: Cedars-Sinai Medical Center
Xen Ping Hoi: Cedars-Sinai Medical Center
Mark Ellie Alonzo: Cedars-Sinai Medical Center
Qianxing Mo: H. Lee Moffitt Cancer Center and Research Institute
Armine Kasabyan: Cedars-Sinai Medical Center
Hideki Furuya: Cedars-Sinai Medical Center
Jane Trepel: National Cancer Institute
Dolores Vizio: Cedars-Sinai Medical Center
Jlenia Guarnerio: Cedars-Sinai Medical Center
Dan Theodorescu: Cedars-Sinai Medical Center
Charles Rosser: Cedars-Sinai Medical Center
Andrea Apolo: National Cancer Institute
Matthew Galsky: Icahn School of Medicine at Mount Sinai
Keith Syson Chan: Cedars-Sinai Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29026-9

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