Presentation Authors: Karen Wheeler*, Neelam Mukherjee, Niannian Ji, Robert Svatek, San Antonio, TX
Introduction: Bladder cancer (BC) remains one of the deadliest of all genitourinary cancers. The mainstay of treatment remains radical cystectomy. Recent success of adjuvant anti-PDL1 immunotherapy after surgery for lung cancer has infused interest in post-operative immunotherapy following radical cystectomy and several adjuvant trials are underway. However, surgery itself causes immune dysregulation, which could influence the response to adjuvant immune therapy. The influence of surgery on subsequent immunotherapy is unknown.
Methods: C57BL/6 mice were challenged with BC and then subjected to anesthesia with or without surgery (2 cm laparotomy) under sterile conditions. Metastatic cancer was induced by injecting 0.5 x 106 MB49 bladder tumor cells via tail vein into male mice on the day of surgery. Orthotopic (bladder) cancer was induced by catheterizing the bladders of female mice and injecting poly-L-lysine followed by 0.08x106 MB49 cells, one day prior to surgery. Anti-PD-L1 was given intraperitoneally on days 1, 7, and 12 after surgery. Mice were followed for survival and necropsy was done at time of death. Immune studies were conducted on spleen and tumor-draining lymph nodes (TDLN) to examine the effect of surgery on T cell phenotypes.
Results: Surgery caused a profound increase in pulmonary and liver metastasis associated with reduced survival in mice challenged with MB49 via tail vein (A). As potential mechanisms, surgery increased the percentage of exhausted splenic T cells characterized by expression of PD-1, TIM-3, and LAG-3 and diminished natural killer (NK) production of the pro-inflammatory cytokines IFN-Î³ and TNF-Î± (B). Surgery alone had no effect on survival of mice that did not receive bladder tumors but did significantly decrease the efficacy of Î±-PD-L1 immunotherapy against orthotopic MB49 bladder tumors (C). As expected, Î±-PD-L1 immunotherapy increased the generation of tumor-specific cells in TDLN, but surgery significantly reduced this effect (D).
Conclusions: Surgical stress dampens NK cell cytotoxic cytokines and promotes bladder cancer metastasis. Surgery also suppresses tumor-specific immunity and clinical response to anti-PD-L1 BC immunotherapy. These findings have important implications for surgical management of BC and the potential efficacy of adjuvant BC immunotherapy.
Source of Funding: AUA Care Foundation Research Grant