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Microbial-derived immunostimulatory small molecule augments anti-PD-1 therapy in lung cancer
Rachel C Newsome1, Huijia Liu1, Bright Agbodzi2
1Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
Abstract:
We previously showed that enrichment of the Bacteroides genus is associated with improved anti-PD-1-mediated tumor therapy. Here, we isolate 183 Bacteroides isolates from the feces of humanized anti-PD-1 responder mice. Supernatants from 6 of 183 isolates stimulate IFNγ production from primary CD8+ T cells. These six isolates (6-consort) enhance anti-PD-1-induced anti-tumor efficacy in syngeneic and orthotopic lung cancer models compared to non-responder feces-colonized mice, an effect dependent on the production of IFNγ. Bioassay-guided fractionation and comparative metabolomics lead to the discovery of an active N-acyl amide (cis-Bac429) produced by Bacteroides. cis-Bac429 stimulates IFNγ production by CD8+ T cells but not synthetic saturated Bac429 (sat-Bac429), indicating structural specificity. Intratumorally administered cis-Bac429, but not sat-Bac429, significantly decreases subcutaneous lung and colon tumor growth in combination with anti-PD-1 therapy and drives IFNγ+ CD8+ T cell tumor infiltration. These findings pave the way for development of Bacteroides-type N-acyl-amides as adjuvant treatments for anti-PD-1-refractory NSCLC.
Insights
Bacteroides bacteria produce a compound, cis-Bac429, that enhances anti-PD-1 cancer therapy by boosting CD8+ T cell responses. This discovery offers a new avenue for treating anti-PD-1-refractory non-small cell lung cancer.
Area of Science:
- Immunology
- Microbiome research
- Cancer therapy
Background:
- The Bacteroides genus is linked to better outcomes in anti-PD-1 cancer therapy.
- Identifying specific microbial factors driving therapeutic responses is crucial.
Purpose of the Study:
- To isolate and characterize Bacteroides species that enhance anti-PD-1 therapy.
- To discover the specific microbial metabolite responsible for this enhancement.
- To evaluate the therapeutic potential of this metabolite in preclinical cancer models.
Main Methods:
- Isolation and culturing of 183 Bacteroides strains from responder mice.
- Assessing supernatant-induced IFNγ production in CD8+ T cells.
- Bioassay-guided fractionation and metabolomics to identify active compounds.
- Testing cis-Bac429 efficacy in syngeneic and orthotopic lung and colon cancer models with anti-PD-1 therapy.
Main Results:
- Six Bacteroides isolates (6-consort) enhanced anti-PD-1 efficacy, dependent on IFNγ production.
- The N-acyl amide cis-Bac429 was identified as the active compound.
- cis-Bac429 specifically stimulated IFNγ production in CD8+ T cells.
- Intratumoral cis-Bac429, combined with anti-PD-1, reduced tumor growth and increased CD8+ T cell infiltration.
Conclusions:
- cis-Bac429 is a novel Bacteroides-derived metabolite that enhances anti-PD-1 therapy by promoting CD8+ T cell responses.
- These findings support the development of Bacteroides-type N-acyl-amides as adjuvants for anti-PD-1-refractory non-small cell lung cancer.
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