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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells

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Engineered Bacteria Increase L-Arginine to Improve Immunotherapy Response

Cancer Discovery

|October 16, 2021

Summary

Engineered bacteria boost intratumoral L-arginine levels, enhancing the effectiveness of immune checkpoint therapies for cancer treatment. This approach offers a novel strategy to improve anti-tumor immunity.

Area of Science:

Biotechnology
Immunology
Microbiology

Background:

Immune checkpoint therapies (ICTs) have revolutionized cancer treatment but response rates remain limited.
L-arginine is crucial for T-cell function and its depletion in the tumor microenvironment (TME) impairs anti-tumor immunity.
Strategies to increase intratumoral L-arginine are needed to enhance ICT efficacy.

Purpose of the Study:

To engineer bacteria to increase intratumoral L-arginine levels.
To evaluate the synergistic effect of bacteria-mediated L-arginine increase with immune checkpoint blockade.

Main Methods:

Genetic engineering of bacteria (e.g., E. coli Nissle 1917) to overexpress argininosuccinate synthetase (ASS1).
Intratumoral administration of engineered bacteria in a murine tumor model.

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Assessment of L-arginine levels in the TME via liquid chromatography-mass spectrometry.

Evaluation of anti-tumor immune responses, including T-cell infiltration and activation, using flow cytometry and immunohistochemistry.

Combination therapy with anti-PD-1 antibody.

Main Results:

Engineered bacteria successfully colonized the TME and significantly increased L-arginine concentrations.
Increased L-arginine levels correlated with enhanced T-cell function and reduced tumor growth.
Combination of engineered bacteria and anti-PD-1 antibody demonstrated superior anti-tumor efficacy compared to monotherapies.
The synergistic effect was associated with increased CD8+ T-cell infiltration and effector function.

Conclusions:

Engineered bacteria represent a viable platform for augmenting intratumoral L-arginine.
Bacteria-mediated L-arginine increase synergizes with immune checkpoint blockade, enhancing anti-tumor immunity.
This approach holds promise for improving the efficacy of cancer immunotherapy.