Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer. Issue 10 (19th August 2019)

• Record Type: Journal Article
• Authors: Miyake, Makito; Hori, Shunta; Ohnishi, Sayuri; Toritsuka, Michihiro; Fujii, Tomomi; Shimizu, Takuto; Owari, Takuya; Morizawa, Yosuke; Gotoh, Daisuke; Itami, Yoshitaka; Nakai, Yasushi; Anai, Satoshi; Torimoto, Kazumasa; Tanaka, Nobumichi; Fujimoto, Kiyohide
• Is Part Of: Cancer science. Volume 110:Issue 10(2019)
• Page Start: 3315
• Page End: 3327
• Publication Date: 2019-08-19
• Subjects: bladder neoplasm -- colony‐stimulating factor -- local recurrence -- neoadjuvant chemoimmunotherapy -- radical cystectomy; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14158
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Despite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle‐invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony‐stimulating factor (GM‐CSF) to chemoimmunotherapy with programmed cell death protein‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 10 5 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non‐treated control (vehicle only); (ii) anti‐mPD‐L1 monotherapy; (iii) mGM‐CSF monotherapy; (iv) anti‐mPD‐L1 plus mGM‐CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti‐mPD‐L1; (vii) GC plus mGM‐CSF; and (viii) GC plus anti‐mPD‐L1 plus mGM‐CSF. After completing 2‐week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti‐mPD‐L1 and mGM‐CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti‐mPD‐L1, and mGM‐CSF resulted in longer LR‐free survival and cancer‐specific survival compared to those in other groups. These effects involved an immunotherapy‐related decrease in oncological properties such as tumor invasion capacity and epithelial‐mesenchymal transition. mGM‐CSF significantly decreased the accumulation of myeloid‐derived suppressor cells in both the blood and tumor microenvironment and blood interleukin‐6 levels. Supplementary GM‐CSF to neoadjuvant GC plus PD‐L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment. Abstract : Given that a substantial proportion of patients with muscle‐invasive bladder cancer develop local tumor recurrence after radical cystectomy, perioperative treatment strategies should be improved. Our results provided, for the first time, that GM‐CSF supplementation with neoadjuvant gemicitabine/cisplatin plus PD‐L1 blockade could decrease local recurrence after radical surgery by immune modulation in the blood and tumor microenvironment.