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.

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy

“…13 However, opposite results have been described in bladder cancer, with negative chemoimmunotherapy phase III trials, supported by studies in animals models showing that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constrains their antitumoral activity. 33 It is important to identify the patients that will benefit the most from chemoimmunotherapy achieving complete pathological responses and patients with non-CPR tumors that present a higher risk of relapse after surgery. In this regard, we found for the first time a relationship between higher levels of AKT1 in post-treatment tumor samples and a higher risk of progression and death.…”

“… 13 However, opposite results have been described in bladder cancer, with negative chemoimmunotherapy phase III trials, supported by studies in animals models showing that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constrains their antitumoral activity. 33 …”

Strategies to overcome DC dysregulation in the tumor microenvironment

“…There is also an ongoing clinical trial involving the inhibition of PD-1 and VEGF in microsatellite-stable endometrial cancer ( 126 ). PGE2 inhibitors, such as celecoxib, are currently under development in pre-clinical models ( 127 – 129 ). Inhibition of several tumor immunosuppressive cytokines blocking the inflammasome pathway are also in the clinic or under development, such as anti-IL-1bR, anti-IL-1, IRAK4 ( 130 , 131 ) and IL-6 inhibitors ( 132 ).…”

Immunogenic Cell Death Role in Urothelial Cancer Therapy

“…This type of damage-associated molecular pattern is shown to reverse the effect of DAMPs by reducing the immunogenicity of the cell death [ 53 ]. Nikolos et al [ 40 ] showed that inhibition of prostaglandin-E2, a known iDAMP, increases ICD and turns chemo-immunotherapy unresponsive tumors into T-cell inflamed responsive tumors. The same authors previously showed concomitant release of iDAMP and DAMP as a mechanism of ICD resistance and failure of AVE generation when gemcitabine was added to chemotherapy regimen [ 39 ].…”