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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   MBT 2 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.

cancer science

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer