TY - JOUR
T1 - Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy
AU - Anker, Jonathan F.
AU - Naseem, Anum F.
AU - Mok, Hanlin
AU - Schaeffer, Anthony J.
AU - Abdulkadir, Sarki A.
AU - Thumbikat, Praveen
N1 - Funding Information:
We thank the members of the P.T. and S.A.A. laboratories, B. Zhang, M. Brown, and D. Wainwright for their support, the DNA/RNA Delivery Core of the Skin Disease Research Center of Northwestern University for their assistance with CRISPR, S. Swaminathan and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core for help with designing the flow cytometry staining panels, M. Sebastian and the MD Anderson Cancer Center Histology, Pathology, and Imaging Core (supported by P30 CA16672 DHHS/NCI Cancer Center Support Grant) for blinded IHC staining and scoring, S. Murphy for bacterial genomic DNA preparation, and B. Wray and the NUSeq Core facility at Northwestern University for assistance with bacterial whole-genome sequencing. This work was supported by National Institutes of Health grants to J.F.A. (NCI F30 CA203472), S.A.A. (NCI R01 CA167966, NCI R01 CA123484, NCI P50 CA180995), and P.T. (NIDDK R01 DK094898, NIDDK R01 DK108127).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Immune checkpoint inhibitors have not been effective for immunologically "cold" tumors, such as prostate cancer, which contain scarce tumor infiltrating lymphocytes. We hypothesized that select tissue-specific and immunostimulatory bacteria can potentiate these immunotherapies. Here we show that a patient-derived prostate-specific microbe, CP1, in combination with anti-PD-1 immunotherapy, increases survival and decreases tumor burden in orthotopic MYC- and PTEN-mutant prostate cancer models. CP1 administered intra-urethrally specifically homes to and colonizes tumors without causing any systemic toxicities. CP1 increases immunogenic cell death of cancer cells, T cell cytotoxicity, and tumor infiltration by activated CD8 T cells, Th17 T cells, mature dendritic cells, M1 macrophages, and NK cells. CP1 also decreases intra-tumoral regulatory T cells and VEGF. Mechanistically, blocking CP1-recruited T cells from infiltrating the tumor inhibits its therapeutic efficacy. CP1 is an immunotherapeutic tool demonstrating how a tissue-specific microbe can increase tumor immunogenicity and sensitize an otherwise resistant cancer type to immunotherapy.
AB - Immune checkpoint inhibitors have not been effective for immunologically "cold" tumors, such as prostate cancer, which contain scarce tumor infiltrating lymphocytes. We hypothesized that select tissue-specific and immunostimulatory bacteria can potentiate these immunotherapies. Here we show that a patient-derived prostate-specific microbe, CP1, in combination with anti-PD-1 immunotherapy, increases survival and decreases tumor burden in orthotopic MYC- and PTEN-mutant prostate cancer models. CP1 administered intra-urethrally specifically homes to and colonizes tumors without causing any systemic toxicities. CP1 increases immunogenic cell death of cancer cells, T cell cytotoxicity, and tumor infiltration by activated CD8 T cells, Th17 T cells, mature dendritic cells, M1 macrophages, and NK cells. CP1 also decreases intra-tumoral regulatory T cells and VEGF. Mechanistically, blocking CP1-recruited T cells from infiltrating the tumor inhibits its therapeutic efficacy. CP1 is an immunotherapeutic tool demonstrating how a tissue-specific microbe can increase tumor immunogenicity and sensitize an otherwise resistant cancer type to immunotherapy.
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U2 - 10.1038/s41467-018-03900-x
DO - 10.1038/s41467-018-03900-x
M3 - Article
C2 - 29686284
AN - SCOPUS:85045994857
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1591
ER -
