Final Report Summary - UPECBCG (Cellular and molecular mechanisms of bladder immune responses to uropathogens and therapeutics)
This project addressed mechanisms of innate and adaptive mucosal immunity, including how specific innate immune cell populations shape the initiation and development of immunity and how immunotherapeutic approaches alter the host response to improve immunity. To answer these questions, we studied urinary tract infection (UTI) and immunotherapy for non-muscle invasive bladder cancer (NMIBC). These diseases are highly prevalent, with major health care-associated costs. Exploring these two different diseases will broaden our understanding of mucosal immunity from a unique barrier organ, enable us to test cross-disciplinary concepts in a single tissue, such as the application of cancer immunotherapy as non-antibiotic therapy for recurrent infection, and provide a foundation for further therapeutic innovation.
Within the context of this project, we identified innate immune components shaping host response to UTI through novel approaches, such as bladder tissue multi-analyte analysis and cytometry and fluorescent uropathogens, to address why UTI recur in up to 25% of all women. We showed that immune cells, including monocytes, or MAIT cells (with Dr. Olivier Lantz, Institut Curie), contribute to resolution of infection. We reported that macrophages are the most populous bladder resident immune cell and the cell type phagocytizing a majority of bacteria early in UTI. We found that adaptive immunity, dependent on DCs and T cells, develops during UTI, but does not confer sterilizing immunity to challenge infection. We observed improved, T cell dependent protection after transient resident macrophage depletion and concomitant increased bacterial uptake by DCs.
We also dissected Gram-positive (G+) uropathogen pathogenesis and defined a preventative approach for catheter-associated UTI. Uropathogenic E. coli (UPEC) is the primary cause of UTI, however G+ bacteria, which are frequently overlooked in polymicrobial UTI, induce significant morbidity. They are particularly important in catheter-associated UTI, the most common hospital-associated infection. Together with Dr. Kimberly Kline (NTU, Singapore) we showed that G+ E. faecalis promotes immune suppression in the bladder to enhance infection by other microbes. In an indwelling catheter-associated UTI model, we demonstrated that a single, short-acting prophylactic dose of antibiotics inhibits bladder and catheter colonization by UPEC and E. faecalis.
Finally, we identified mechanisms to optimize preclinical and clinical responses to bladder cancer immunotherapy. BCG immunotherapy has been used for 40 years to induce specific tumor immunity in bladder cancer, however clinically available BCG strains differ at the genetic level. We tested the impact of these differences on induction of immunity, finding that the BCG Connaught strain drives stronger beneficial Th1-biased responses, and greater BCG-specific CD8+ T cell priming and T cell infiltration in mice compared to BCG Tice. In patients, 5-year tumor recurrence-free survival was 75% in those treated with BCG Connaught compared to 46% in Tice-treated patients. Patients do not always benefit from BCG, however, and additional immunotherapeutic approaches are needed. In a subcutaneous tumor model, we found that inhibiting the enzyme CD26 (which inactivates chemokines by cleavage) preserves the agonist form of CXCL10, increases T cell infiltration to tumor sites, and enhances tumor rejection in combination with immune checkpoint inhibiton.
Take together, these data show a complex interplay among immune cells in the bladder and reveal novel targets, such as macrophages or CD26, to enhance protective immunity to UTI or improve response to therapy in cancer. This work has also led to a greater appreciation of G+ organisms in UTI, established that uropathogens can directly manipulate bladder immunity, and proposed a preventative approach for a major public health concern.
Within the context of this project, we identified innate immune components shaping host response to UTI through novel approaches, such as bladder tissue multi-analyte analysis and cytometry and fluorescent uropathogens, to address why UTI recur in up to 25% of all women. We showed that immune cells, including monocytes, or MAIT cells (with Dr. Olivier Lantz, Institut Curie), contribute to resolution of infection. We reported that macrophages are the most populous bladder resident immune cell and the cell type phagocytizing a majority of bacteria early in UTI. We found that adaptive immunity, dependent on DCs and T cells, develops during UTI, but does not confer sterilizing immunity to challenge infection. We observed improved, T cell dependent protection after transient resident macrophage depletion and concomitant increased bacterial uptake by DCs.
We also dissected Gram-positive (G+) uropathogen pathogenesis and defined a preventative approach for catheter-associated UTI. Uropathogenic E. coli (UPEC) is the primary cause of UTI, however G+ bacteria, which are frequently overlooked in polymicrobial UTI, induce significant morbidity. They are particularly important in catheter-associated UTI, the most common hospital-associated infection. Together with Dr. Kimberly Kline (NTU, Singapore) we showed that G+ E. faecalis promotes immune suppression in the bladder to enhance infection by other microbes. In an indwelling catheter-associated UTI model, we demonstrated that a single, short-acting prophylactic dose of antibiotics inhibits bladder and catheter colonization by UPEC and E. faecalis.
Finally, we identified mechanisms to optimize preclinical and clinical responses to bladder cancer immunotherapy. BCG immunotherapy has been used for 40 years to induce specific tumor immunity in bladder cancer, however clinically available BCG strains differ at the genetic level. We tested the impact of these differences on induction of immunity, finding that the BCG Connaught strain drives stronger beneficial Th1-biased responses, and greater BCG-specific CD8+ T cell priming and T cell infiltration in mice compared to BCG Tice. In patients, 5-year tumor recurrence-free survival was 75% in those treated with BCG Connaught compared to 46% in Tice-treated patients. Patients do not always benefit from BCG, however, and additional immunotherapeutic approaches are needed. In a subcutaneous tumor model, we found that inhibiting the enzyme CD26 (which inactivates chemokines by cleavage) preserves the agonist form of CXCL10, increases T cell infiltration to tumor sites, and enhances tumor rejection in combination with immune checkpoint inhibiton.
Take together, these data show a complex interplay among immune cells in the bladder and reveal novel targets, such as macrophages or CD26, to enhance protective immunity to UTI or improve response to therapy in cancer. This work has also led to a greater appreciation of G+ organisms in UTI, established that uropathogens can directly manipulate bladder immunity, and proposed a preventative approach for a major public health concern.