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Background The intratumoral microbiome has recently emerged as a new hallmark of cancer, with implications for response or resistance to therapy. While bacteria can either promote or inhibit cancer growth, intratumoral bacteria can also be engineered using synthetic biology to remodel the tumor microenvironment.Methods Here, we engineered the probiotic bacterium E. coliNissle 1917 (EcN) to express the human chemokine CXCL13, a critical component of germinal center (GC) formation. The GC reaction is a fundamental aspect of adaptive immunity by which antibody affinity develops in secondary lymphoid organs for defense against pathogens.Results Using orthotopic models of bladder cancer, engineered CXCL13-expressing EcN colonized bladder tumors and elicited GC responses in bladder tumor-draining lymph nodes after intravesical delivery. Furthermore, when combined with PD-1 blockade, engineered EcN amplified the antitumor antibody response and promoted long-term survival and protective immunity upon tumor rechallenge ( figure 1). Here, we demonstrate that intravesically delivered EcNhCXCL13 promote GC responses that augment the production of antitumor IgG antibodies upon combination with PD-1 blockade, which in turn enhances ICB therapeutic efficacy (figure 2).Conclusions Thus, we show that synthetically engineered CXCL13-expressing EcN can enhance the efficacy of PD-1 checkpoint blockade immunotherapy by amplifying tumor-specific humoral immunity.Acknowledgements We thank Shane Crotty for providing bone marrow from Bcl6fl/flCD4-cre BL/6 mice, William Kim for providing the UPPL1541 cell line, and James M. McKiernan for providing the BCG vials. We are thankful for insightful discussion with the members of the Arpaia and Danino labs. We thank the members of the Mendelsohn lab for providing technical support with the orthotopic UPPL1541 model. This research used the resources of the Oncology Precision Therapeutics and Imaging Core at the Herbert Irving Comprehensive Cancer Center, and the Histology Service at the Columbia University Irving Medical Center. This work was supported by NIH/NCI R01CA249160, NIH/NCI R01CA259634, NIH/NCI U01CA247573 (NA/TD), and the Charles H. Revson Foundation (MR).Ethics Approval All experiments were performed in compliance with institutional guidelines and were approved by the Columbia University Institutional Animal Care and Use Committee (protocol AC-AABD8554). Seven-week-old wild-type C57BL/6NJ mice were purchased from the Jackson Laboratory, allowed to acclimate for a week, and then injected with cancer cells. Mice were randomized into treatment groups. All mice used were 8 to 12-week-old at time of experiment. Mice were housed at the Herbert Irving Comprehensive Cancer Center or at the Hammer Health Sciences Building under specific pathogen-free conditions.Abstract 936 Figure 1EcNhCXCL13 synergizes with PD-1 blockade to promote long-term survival and durable protection in an orthotopic model of advanced bladder cancerAbstract 936 Figure 2EcNhCXCL13 plus PD-1 blockade boosts the production of IgG antitumor antibodies