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

Cancers

卷:13

PerH. Basse¹  Weijian Jiang¹  OmarM. Ibrahim¹  Pawel Kalinski¹  Gurkamal Chatta²  Khurshid Guru² 

[1] Department of Medicine and Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;

[2] Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;

关键词: chemokines;    tumor microenvironment (TME);    Bacillus Calmette–Guérin (BCG);    bladder cancer;    immunomodulation;    immunotherapy;   

DOI  :  10.3390/cancers13061323

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown