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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell
Fotis Nikolos1, Kazukuni Hayashi2,3, Xen Ping Hoi1,4
1Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
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.
Insights
Platinum chemotherapy hinders anti-tumor T cells in bladder cancer. Blocking prostaglandin E2 (PGE2) restores T cell activity and enhances immunotherapy response.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Chemoimmunotherapy shows limited success in advanced bladder cancer.
- Mechanisms for poor response, particularly drug-induced ones, are not fully understood.
- Tumor-intrinsic "immune-excluded" properties are often the focus, neglecting drug effects.
Purpose of the Study:
- Investigate a drug-induced mechanism limiting chemoimmunotherapy efficacy in bladder cancer.
- Explore how chemotherapy affects T cell infiltration and anti-tumor activity.
- Identify strategies to overcome chemotherapy resistance and enhance immunotherapy.
Main Methods:
- Utilized two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC).
- Administered platinum-based chemotherapy and assessed CD8+ T cell infiltration and activity.
- Investigated the role of prostaglandin E2 (PGE2) release from chemotherapy-induced dying cancer cells.
- Evaluated the effect of pharmaceutical blockade of PGE2 on T cell response and tumor inflammation.
- Assessed the combination of PGE2 blockade, chemotherapy, and anti-PD1 therapy.
Main Results:
- Platinum chemotherapy reduced CD8+ T cell infiltration and anti-tumor activity in MIBC models.
- Chemotherapy induced prostaglandin E2 (PGE2) release, an inhibitory damage-associated molecular pattern (iDAMP).
- PGE2 inhibited dendritic cell maturation, impairing T cell responses.
- Pharmaceutical blockade of PGE2 restored CD8+ T cell tumor infiltration and anti-tumor function.
- Blocking PGE2 synergized with chemotherapy and sensitized tumors to anti-PD1 therapy.
Conclusions:
- Chemotherapy-induced PGE2 release is a key mechanism of resistance in bladder cancer.
- Blocking PGE2 ('iDAMP blockade') can overcome chemotherapy-induced immune suppression.
- Combining chemotherapy with PGE2 blockade and anti-PD1 immunotherapy offers a promising strategy for advanced bladder cancer.
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