NFκB-Activated COX2/PGE2/EP4 Axis Controls the Magnitude and Selectivity of BCG-Induced Inflammation in Human Bladder Cancer Tissues

Abstract

Bacillus Calmette-Guérin (BCG) is commonly used in the immunotherapy of bladder cancer (BlCa) but its effectiveness is limited to only a fraction of patients. To identify the factors that regulate the response of human BlCa tumor microenvironment (TME) to BCG, we used the ex vivo whole-tissue explant model. The levels of COX2 in the BCG-activated explants closely correlated with the local production of Treg- and MDSCS attractants and suppressive factors, while the baseline COX2 levels did not have predictive value. Accordingly, we observed that BCG induced high levels of MDSC- and Treg-attracting chemokines (CCL22, CXCL8, CXCL12) and suppressive factors (IDO1, IL-10, NOS2). These undesirable effects were associated with the nuclear translocation of phosphorylated NFκB, induction of COX2, the key enzyme controlling PGE2 synthesis, and elevation of a PGE2 receptor, EP4. While NFκB blockade suppressed both the desirable and undesirable components of BCG-driven inflammation, the inhibitors of PGE2 synthesis (Celecoxib or Indomethacin) or signaling (EP4-selective blocker, ARY-007), selectively eliminated the induction of MDSC/Treg attractants and immunosuppressive factors but enhanced the production of CTL attractants, CCL5, CXCL9 and CXCL10. PGE2 blockade allowed for the selectively enhanced migration of CTLs to the BCG-treated BlCa samples and eliminated the enhanced migration of Tregs. Since the balance between the CTLs and suppressive cells in the TME predicts the outcomes in patients with BlCa and other diseases, our data help to elucidate the mechanisms which limit the effectiveness of BCG therapies and identify new targets to enhance their therapeutic effects.

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“…For example, in non-small cell lung cancer, CCL7 was an immune-related prognostic biomarker r and adjuvant in uencing the tumor microenvironment [19]. PGE2/EP4 Axis can promote immune suppression and Tregs attraction in BCG-exposed human bladder cacer tissues [20]. According to relevant literature, LNCRNA also plays an important role in many types of cancer.…”

Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions

“…Furthermore, NF-κB and IL-6 could support the stemness of some cancer cells or induce chemotherapy resistance [ 62 , 63 ]. NF-κB-activated cyclooxygenase-2 has been shown to regulate the magnitude and selectivity of inflammation induced by Bacillus Calmette-Guérin in bladder cancer [ 64 ]. In addition, tumor necrosis factor-α mediates the interaction between gastric cancer cells and activated fibroblasts, possibly contributing to tumor metastasis [ 65 ].…”

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“…However, while separating or isolating the active material that includes it, poisonous compounds and impurities are introduced owing to isolation techniques which use chemicals and separated instruments to accompany the active ingredient, resulting in toxicity during treatment. Usually, upon extraction of active ingredients from medicinal plants, processing is needed to enhance various characteristics; in some cases, such as with Flavonoids, processing can introduce toxic byproducts [79][80][81][82][83][84][85][86][87][88][89][90].…”