Enhancing Bacterial Iron Acquisition Overcomes Nutritional Immunity for Effective Cancer Therapy

Core Concepts

Enhancing the iron-scavenging capability of bacteria can overcome the host's nutritional immunity and significantly improve the anti-tumor efficacy of bacterial cancer therapy.

Abstract

The study aimed to understand how bacteria adapt to the tumor microenvironment (TME) at the molecular level and leverage this knowledge to enhance bacterial cancer therapy.
Key highlights:

Quantitative proteomic analysis revealed that the TME is an iron-deficient environment for E. coli, leading to upregulation of proteins involved in iron homeostasis and enterobactin biosynthesis. This iron deficiency triggers the host to secrete the iron-sequestering protein lipocalin 2 (LCN2) as a nutritional immunity response.

To overcome this nutritional immunity, the researchers engineered E. coli to express the IroA gene cluster, which enables the synthesis of glycosylated enterobactin that can evade LCN2 sequestration. This IroA-E. coli showed enhanced resistance to LCN2 and significantly improved anti-tumor activity in multiple mouse tumor models compared to wild-type E. coli.

The IroA-E. coli treatment also stimulated robust anti-tumor adaptive immunity, leading to complete tumor regression and resistance to tumor re-challenge in mice.

Combining the IroA-E. coli with the iron chelator oxaliplatin further enhanced the anti-tumor efficacy through a synergistic mechanism when delivered systemically.

Overall, the study highlights the crucial role of bacterial iron acquisition in the TME for effective cancer therapy and provides a strategy to overcome the host's nutritional immunity by engineering bacteria with enhanced iron-scavenging capabilities.

Stats

E. coli colonized in tumors showed 2-5 fold upregulation in proteins involved in enterobactin biosynthesis and iron ion homeostasis compared to E. coli cultured in rich medium.
Tumors with E. coli inoculation had a significant 2-fold increase in the expression of the iron-sequestering protein lipocalin 2 (LCN2) compared to tumors without E. coli.
The IroA-E. coli showed 2-3 fold higher resistance to LCN2 inhibition compared to wild-type E. coli.
The IroA-E. coli treatment achieved complete tumor regression in 6 out of 10 mice in the MC38 colon cancer model, while the wild-type E. coli had no complete remissions.

Quotes

"Enhancing the iron-scavenging capability of bacteria can overcome the host's nutritional immunity and significantly improve the anti-tumor efficacy of bacterial cancer therapy."
"The study highlights the crucial role of bacterial iron acquisition in the tumor microenvironment for effective cancer therapy and provides a strategy to overcome the host's nutritional immunity by engineering bacteria with enhanced iron-scavenging capabilities."

Key Insights Distilled From

Overcoming the nutritional immunity by engineering iron scavenging bacteria for cancer therapy

by Huang,S.-W.,... at www.biorxiv.org 07-27-2023

https://www.biorxiv.org/content/10.1101/2023.07.25.550605v3

Deeper Inquiries

How could the engineered IroA-E. coli be further optimized to enhance its anti-tumor potency and safety profile for clinical translation?

To further optimize the engineered IroA-E. coli for enhanced anti-tumor potency and safety in clinical translation, several strategies can be considered:

Enhanced Iron Scavenging: Continuously improving the ability of IroA-E. coli to scavenge iron in the tumor microenvironment can enhance its anti-tumor potency. This could involve optimizing the expression levels of the IroA cluster genes responsible for glycosylating enterobactin or exploring additional iron acquisition pathways to outcompete host cells for iron.

Targeted Delivery: Developing methods for targeted delivery of IroA-E. coli specifically to tumor sites can improve its efficacy while minimizing off-target effects. This could involve engineering the bacteria to respond to specific tumor microenvironment cues for precise localization.

Immunomodulation: Modulating the immune response within the tumor microenvironment can enhance the anti-tumor activity of IroA-E. coli. This could involve incorporating additional immunomodulatory factors into the bacteria to stimulate the immune system's response against cancer cells.

Safety Enhancements: Ensuring the safety profile of IroA-E. coli is crucial for clinical translation. Strategies to enhance safety could include further studies on potential off-target effects, optimizing dosing regimens, and exploring methods for bacterial clearance post-treatment.

Combination Therapies: Investigating the synergistic effects of combining IroA-E. coli with other treatment modalities, such as chemotherapy or immunotherapy, can further enhance its anti-tumor potency while potentially reducing the risk of resistance development.

How might manipulating iron metabolism in the tumor microenvironment more broadly impact cancer progression and treatment response?

Manipulating iron metabolism in the tumor microenvironment can have significant implications for cancer progression and treatment response:

Tumor Growth Inhibition: By targeting iron availability in the tumor microenvironment, the growth and proliferation of cancer cells can be inhibited. Iron is essential for cell division and growth, so limiting its availability can slow down tumor progression.

Enhanced Treatment Efficacy: Manipulating iron metabolism can sensitize cancer cells to existing treatments, such as chemotherapy or radiation therapy. Iron chelation therapy, for example, can make cancer cells more vulnerable to these treatments, leading to improved treatment outcomes.

Immune Response Modulation: Iron plays a crucial role in immune cell function, and altering iron metabolism in the tumor microenvironment can modulate immune responses. This can impact the tumor immune microenvironment and potentially enhance anti-tumor immune responses.

Resistance Prevention: Cancer cells often exhibit altered iron metabolism, leading to increased iron uptake. By targeting iron metabolism, it may be possible to overcome mechanisms of treatment resistance that rely on iron-dependent pathways.

Therapeutic Opportunities: Developing novel therapies that specifically target iron metabolism in tumors can open up new avenues for cancer treatment. This could include the use of iron chelators, iron scavenging bacteria, or other targeted approaches to disrupt iron homeostasis in cancer cells.

Overall, manipulating iron metabolism in the tumor microenvironment presents a promising strategy for impacting cancer progression and improving treatment responses through a multifaceted approach.

What other host defense mechanisms, beyond nutritional immunity, might limit the therapeutic efficacy of bacteria in the tumor microenvironment, and how could they be addressed?

In addition to nutritional immunity, several other host defense mechanisms can limit the therapeutic efficacy of bacteria in the tumor microenvironment:

Immune Evasion: The host immune system can recognize and eliminate bacteria, limiting their colonization and anti-tumor effects. Strategies to address immune evasion could involve engineering bacteria to evade immune detection or modulate immune responses to promote tumor targeting.

Biofilm Formation: Bacteria can form biofilms in the tumor microenvironment, which can protect them from host immune responses and antimicrobial treatments. Disrupting biofilm formation or enhancing bacterial susceptibility to biofilm-disrupting agents can address this limitation.

Toxicity: Bacteria-based therapies can induce toxic effects in the host, leading to adverse reactions and limiting their clinical application. Strategies to mitigate toxicity could involve optimizing dosing regimens, enhancing bacterial clearance post-treatment, or developing bacteria with reduced virulence.

Competition with Commensal Microbiota: The presence of commensal bacteria in the tumor microenvironment can compete with therapeutic bacteria for nutrients and colonization sites. Addressing this competition may involve engineering bacteria with enhanced nutrient acquisition capabilities or developing strategies to selectively target cancer cells.

Tumor Heterogeneity: Tumors are heterogeneous environments with varying oxygen levels, pH, and nutrient availability. This heterogeneity can impact the distribution and efficacy of bacteria-based therapies. Tailoring treatment strategies to account for tumor heterogeneity can improve therapeutic outcomes.

By understanding and addressing these additional host defense mechanisms, researchers can optimize bacteria-based therapies for enhanced efficacy and safety in the complex tumor microenvironment.