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Principal Investigator: Howard C Hang
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $527,560
Funding agency: National Cancer Institute
PROJECT SUMMARY
Microbiota are associated with remarkable effects on host health and disease. Notably, discrete species of
commensal bacteria have been correlated with improved patient responses to cancer immunotherapy. However,
the molecular mechanisms underlying the functions of these beneficial bacteria remain poorly understood. In
particular, specific strains of Enterococci have been linked with improved response to anti-PD-1/PD-L1 treatment
in patients with metastatic melanoma, lung, and kidney cancers, but their mechanism of action has not been
elucidated nor employed to improve cancer immunotherapy. Recent work from the Hang laboratory has
demonstrated that these beneficial strains of Enterococci have unique peptidoglycan composition and
remodeling enzymes. Based on these studies, this project hypothesizes that specific strains of Enterococci may
prime innate immune signaling pathways and enhance anti-PD-1/PD-L1 immunotherapy against metastatic
cancers. To evaluate the activity and mechanism(s) of Enterococci during immunotherapy as well as co-opt their
protective factors for cancer immunotherapy, this proposal will examine how specific Enterococci strains alter
cancer growth, immune cell populations, and microbiota composition in mouse models of cancer immunotherapy.
In addition, the Hang laboratory will identify Enterococci protective factors and engineer them into existing human
probiotics to translate our basic microbiota-cancer immunotherapy findings into novel therapeutic agents. Finally,
the Hang laboratory will also synthesize novel immunomodulatory small molecules that activate host pathways
used by Enterococci to enhance cancer immunotherapy. These studies will reveal fundamental microbiota-
cancer immunotherapy mechanisms and develop new therapeutic strategies and agents to enhance cancer
immunotherapy.
Terms: <Animal Model><Animal Models and Related Studies><Attenuated><Bacteria><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell Wall><Cells><Checkpoint inhibitor><Chemicals><Disease><Disorder><Disseminated Malignant Neoplasm><Drugs><E durans><E faecium><E. durans><E. faecium><Endopeptidases><Engineered Probiotics><Engineering><Enterococcus><Enterococcus durans><Enterococcus faecium><Enzyme Gene><Enzymes><Farm Animal><Generalized Growth><Growth><Health><Human><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immune signaling><Immunes><Immunity><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><Individual><Kidney Cancer><Kidney Carcinoma><Laboratories><Large-Scale Sequencing><Link><Livestock><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Medication><Melanoma><Melanoma Metastasis><Metastatic Cancer><Metastatic Malignant Neoplasm><Metastatic Melanoma><Modern Man><Modified Probiotics><Molecular><Murein><PD-1 antibody therapy><PD-1 therapy><PD-L1 therapy><PD-L1 treatment><PD1 antibody therapy><PD1 based treatment><PDL1 therapy><PDL1 treatment><Pathway interactions><Patients><Pattern recognition receptor><Peptide Peptidohydrolases><Peptidoglycan><Pharmaceutical Preparations><Population><Probiotic Engineering><Probiotics><Pulmonary Cancer><Pulmonary malignant Neoplasm><Renal Cancer><Renal Carcinoma><Resistance><Role><S faceium><S faecium><S. faceium><S. faecium><Signal Pathway><Streptococcus enterococcus group><Streptococcus faceium><Streptococcus faecium><Therapeutic><Therapeutic Agents><Tissue Growth><Translating><Translations><Work><aCTLA-4><aCTLA4><aPD-1 therapy><aPD-1 treatment><aPD-L1 therapy><aPD-L1 treatment><aPD1 therapy><aPD1 treatment><analog><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-CTLA-4><anti-CTLA4><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD-1/PD-L1><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PD1 therapy><anti-PD1 treatment><anti-PDL1 therapy><anti-PDL1 treatment><anti-cancer immunotherapy><anti-cancer therapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1 therapy><anticancer immunotherapy><attenuate><attenuates><bowel inflammation><cancer immunotherapy><cancer therapy><cancer-directed therapy><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><clinical efficacy><commensal bacteria><commensal bacterial species><commensal community><commensal microbiome><commensal species><drug/agent><enteral infection><enteral pathogen><enteric infection><enteric pathogen><enteric pathogen infection><enteropathogen><enteropathogen infection><enteropathogenic infection><gut inflammation><host microbiota><host microflora><host response><human model><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><infected with enteropathogen><inflamed bowel><inflamed gut><inflamed intestine><intestinal barrier><intestinal infection><intestinal inflammation><intestinal mucosal barrier><intestinal pathogen><intestine infection><intestine pathogen><lactic acid bacteria><lung cancer><malignancy><microbial consortia><microbial flora><microbiota><microbiota composition><microflora><model of animal><model of human><mouse model><multispecies consortia><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><pathway><patient response><patient specific response><pet animal><pets><programmed cell death protein 1 therapy><protective factors><resident commensals><resident microbes><resident microflora><resistant><response><responsive patient><small molecule><social role><therapeutic outcome><therapy outcome><translation><α-CTLA-4><α-CTLA4><αCTLA-4><αCTLA4><αPD-L1 therapy><αPD-L1 treatment>