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

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 IFN gamma and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E-2 (PGE(2)) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE(2) 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. Chemoimmunotherapy recently failed to improve objective response for patients with advanced muscle-invasive bladder cancer (MIBC). Here using two murine models of immune-excluded MIBC, the authors show that resistance to chemoimmunotherapy can be overcome by blocking the COX-2/prostaglandin E2 axis, reinvigorating anti-tumor immune responses.

Automated summary

Chemoimmunotherapy has shown limited clinical benefit in bladder cancer patients and the reasons for this are not well understood. This study reveals that platinum-based chemotherapy hinders the infiltration and activity of CD8+ T cells in mouse models of muscle-invasive bladder cancer. The release of prostaglandin E-2 (PGE(2)) from dying cancer cells is identified as a mechanism that inhibits dendritic cell maturation. By blocking PGE(2) release, CD8+ T cells regain their tumoricidal activity and infiltrate the tumor site. Blocking PGE(2) release synergizes with chemotherapy and enhances the response to immune checkpoint inhibitor therapy. These findings highlight the potential of targeting the COX-2/PGE2 axis in chemoimmunotherapy for bladder cancer.