Targeted Antibiotic Therapy for Colon Cancer Developed!

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Targeted Antibiotic Therapy for Colon Cancer Developed!

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Nature Biotechnology: Targeted Antibiotic Therapy for Colon Cancer Developed!

Scientists Create New Anti-Cancer Antibiotic Targeting and Eliminating Colorectal Cancer Bacteria, Activating “Cross-Immunity” in T Cells

The relationship between cancer and microorganisms is well-known in the era of immunotherapy, prompting researchers to explore various cancer-fighting strategies. However, a simpler approach may be effective: eradicating specific microorganisms may be enough to combat cancer!

On Sep 26, in Nature Biotechnology, a team from the University of North Carolina published their latest research showing that using specially designed liposomal antibiotics (with the core component being metronidazole), they can target and eliminate specific bacteria highly associated with the development of colorectal cancer (CRC). This approach activates “cross-immunity” in T cells, allowing them to target both cancer cells and bacteria simultaneously, without disrupting the gut microbiome [1].

Several years ago, groundbreaking research published in Nature and Science demonstrated that human leukocyte antigen (HLA) molecules derived from microorganisms (bacteria or bacteriophages) could also be found on the surface of cancer cells. These molecules can be recognized by T cells, which are naturally tasked with fighting cancer, indicating the presence of “cross-immunity” between microorganisms and cancer [2-3].

Building on this, the North Carolina team hypothesized that killing microorganisms within tumors could expose more shared antigenic epitopes between microorganisms and cancer cells, leading to a better immune response. This concept is somewhat similar to the immune therapy combined with radiation or chemotherapy, where the release of antigens after other treatments sensitizes the immune response.

However, achieving the precise eradication of tumor-associated microorganisms cannot be accomplished with broad-spectrum antibiotics. What is needed is targeted, potent therapy. To address this, the research team developed a novel antibiotic called LipoAgTNZ, which contains a silver-metronidazole complex encapsulated in nano-liposomes for precise delivery to tumor sites.

The choice of metronidazole as the core component was based on an analysis of over 36,000 cases of colorectal cancer patients who had undergone surgery. The study found that patients who had used antibiotics targeting anaerobic microorganisms (such as metronidazole and other nitroimidazole drugs or lincomycin) before surgery had a 25.5% reduced risk of tumor recurrence or death. This effect was comparable to standard adjuvant chemotherapy for colorectal cancer.

Antibiotics targeting anaerobic microorganisms have a “protective effect” on bowel cancer patients

Further experiments and analysis revealed that Fusobacterium nucleatum (F. nucleatum) was the primary bacterium invading colorectal cancer under anaerobic conditions. These bacteria significantly accelerated tumor growth in mice (compared to mice lacking this bacterium) and were found in primary tumors, lymph node invasions, and distant metastases. Therefore, they became the primary target for intervention using LipoAgTNZ.

Fusobacterium nucleatum in intestinal cancer may be of great significance to tumor occurrence and development

Treating colorectal cancer model mice (infected with F. nucleatum) with LipoAgTNZ not only rapidly eliminated F. nucleatum and other resident microorganisms but also increased the long-term survival rate to 71%, significantly higher than the control group. This effect was independent of the presence of F. nucleatum in the gut.

The hypothesis that LipoAgTNZ kills microorganisms and activates an immune response was confirmed. Infiltration of CD3+/CD8+ T cells and CD44+CD62+ memory T cells significantly increased in colorectal cancer, which could resist tumor re-challenge. In contrast, M2-type tumor-associated macrophages, which are detrimental to anti-tumor immunity, decreased significantly. Removing CD4+/CD8+ T cells from the mice before LipoAgTNZ treatment eliminated the therapeutic effect.

LipoAgTNZ treatment can improve the survival rate of intestinal cancer model mice and increase tumor-infiltrating immune cells

LipoAgTNZ also had a similar anti-cancer effect on the most common distant metastasis in colorectal cancer – liver metastasis – by eliminating resident microorganisms. The team also conducted experiments with a combination therapy of antibiotics commonly used to treat F. nucleatum infection (nitroimidazole drugs + cephalosporins) and found that this combination disrupted the gut microbiota and immune response, unlike LipoAgTNZ treatment, which maintained gut microbiota stability.

LipoAgTNZ kills Fusobacterium nucleatum and releases bacterial-derived neoantigens that can be recognized by T cells

Finally, the research team analyzed the entire process of how LipoAgTNZ kills F. nucleatum and activates an immune response, confirming the hypothesis of “cross-immunity” activation of T cells. CD8+ T cells activated by LipoAgTNZ treatment were able to recognize a significant portion of antigenic peptides derived from F. nucleatum (presented by HLA-I class 1 molecules), including those shared between bacteria and colorectal cancer, allowing T cells to target them effectively.

It’s worth noting that immunotherapy for colorectal cancer has previously been less successful, mainly because most colorectal cancers are microsatellite-stable (MSS), lacking newly recognized antigens by the immune system. Therefore, the University of North Carolina team’s research addresses a pressing clinical need. Eliminating microorganisms can transform “cold” tumors into “hot” tumors, offering a promising avenue for the future [1].

Targeted Antibiotic Therapy for Colon Cancer Developed!

Reference:
[1]Wang M, Rousseau B, Qiu K, et al. Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses[J]. Nature Biotechnology, 2023.

[2]Kalaora S, Nagler A, Nejman D, et al. Identification of bacteria-derived HLA-bound peptides in melanoma[J]. Nature, 2021, 592(7852): 138-143.

[3]Fluckiger A, Daillere R, Sassi M, et al. Cross-reactivity between tumor MHC class I–restricted antigens and an enterococcal bacteriophage[J]. Science, 2020, 369(6506): 936-942.

(source:internet, reference only)

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