Clinical:

Intratumoral and Gut Microbiota Roles in Cancer Treatment

By: Ariella Zadrima, PharmD Candidate c/o 2026

Introduction

Cancer is a disease state in which abnormal cells in the body rapidly and uncontrollably divide to destroy body tissue. This growth occurs as a result of genetic changes and can affect many areas and systems of the body. The most common cancers involve breast and lung tissue1. One fundamental feature of cancer is a tumor, which is a solid mass of tissue that forms when abnormal cells group together.  Like the microbiota of the gut, these tumors contain tumor-type-specific intracellular bacteria that can influence the progression of cancer in the body.   Intratumoral bacteria can perform several functions related to cancer pathogenesis, including secreting toxins that can directly damage DNA, 2 or mimicking tumor neoantigens to further activate tumor-specific T cells, aiding in cancer treatment. On the other hand, other microbiota may allow for better regulation of these growths, primarily through modulating tumor-infiltrated myeloid cells. 3 It has been recently discovered that these organisms  may be an effective form of cancer management and treatment when used as an adjunct to chemotherapy.

The microorganisms found in cancerous sites are expected to produce a microenvironment where tumor grows freely, regulate local immunity, and modify tumor cell biology, frequently interfering with a drug’s efficacy and altering the methods by which chemotherapy or anticancer drugs treat an individual’s cancer. Gut microbiota may also be affected by intratumoral microbiota as these cancerous sites, affecting both local and distant tumors, alter the inflammation and metabolism patterns of the tumor. Though researchers are unsure whether these microbiotas can halt the production of cancer or promote it, there are distinct correlations between human microbiomes, and tumor cells.

Microbiota on Immune Response

In one study conducted by the University of Texas MD Anderson Cancer Center, scientists observed the relationship between tumor microbiome diversity and pancreatic cancer outcomes. The team analyzed tumor microbiomes in patients with both short (survival < 5 years post-surgery) and long-term (survival > 5 years post-surgery) survival phases of pancreatic cancer. In patients with long-term survival, it was found that greater microbiome diversity allowed the patient to exhibit high immune activation and combat cancer more efficiently. More specifically, the presence of Saccharopolyspora, Pseudoxanthomonas, and Streptomyces along with Bacillus Clausii was predictive of long-term survival in these patients.  Additionally, using singleplex immunohistochemistry and immunofluorescence staining, the study hypothesizes that tumoral bacteria can shape the immune tumor microenvironment, which can affect the natural history of the cancer. CD8+ T cells were found in significantly greater quantities in long-term survival patients compared to short-term survival patients. A positive correlation was found between CD8+ T cell recruitment and activation and the presence of Saccharopolyspora, Pseudoxanthomonas, and Streptomyces in the tumor.  All in all, the study concluded that in long-term survival patients, a more diverse tumor microbiome may activate immune cells to greater combat cancer.

            Continuing with inflammation factors, the STING signaling pathway, or Stimulator of Interferon Genes, is a process cells undergo to activate host innate immunity, more specifically cytokines, against a pathogen infection that is set to alter DNA and promote cancer growth. It involves cytosolic DNA sending proteins that may activate expression of Interferon B and other inflammatory genes. This pathway plays a key role in propagating the cancer immunity cycle, remodeling the tumor environment, and eliminating all steps to tumorigenesis, whether it be malignant cell transformation or metastasis. 2 In a study conducted by the Department of Radiation and Cellular Oncology, one specific intratumoral microorganism, Lactobacillus rhamnosus GG (LGG), was observed in its efficiency in activating this pathway and prohibiting tumor growth in specific microbiomes like the gut. The study focused on specific cancers such as colorectal carcinoma or melanoma and were induced in murine models with some mice also being administered the intratumoral antibodies against these cancers twice weekly. All mice were also given an oral supplement of LGG to further observe agents against live microbiota environments. It was ultimately concluded that the animals receiving both the intratumoral supplement and the antibody demonstrated a markedly tumor inhibition as compared to either agent used alone upon analyzing the tumor size and survival from the beginning of the experiment. The study reports that this is due to the alteration in gut microbiome caused by the oral supplement; LGG was associated with greater levels of commensal bacteria like Lactobacillus murinus which work to activate antitumor immunity through inducing Cyclic GMP-AMP Synthase and STING-dependent IFN-B production. Furthermore, to further determine the supplement’s effect on IFN-B, the team isolated cytokines produced dendritic cells CXCL 9 and 10. These cytokines are known to be strong mediators of T-cell tumor infiltration and would play a key role in inflammation pathways such as the STING pathway.  It was found that the combination therapy, as well as the monotherapy oral supplement, greatly expanded the population of infiltrating CD11c+ cells. The study ultimately concluded that the combination of lactobacillus rhamnoses GG oral supplements and antibodies greatly activated cytokine cells and interferon cells associated with the STING pathway in efforts to mediate tumor growth, demonstrating how STING pathways and dendritic cells, in specific, play an essential role in antitumor activity when it comes to the live LGG supplement and combination treatment.

Cons of Bacteria in Cancer Therapy

 Though intratumoral microorganisms can promote immunoactivities, it has been shown that some organisms may promote tumor progression. For example, Bacteroides fragilis is an enterotoxigenic bacteria that can lead to increased secretion of interleukin-17 which can promote the infiltration of intratumoral B cells, leading to colon cancer growth.4 These microorganisms can also activate the beta-catenin signal, which promotes cancer stem cell development, an essential cancer intrinsic signal. A prime example of this can be found with the Cytotoxicity-associated immunodominant antigen, a major virulence factor of Helicobacter pylori. This protein can be directly injected into the host’s cytoplasm to activate the beta-catenin signaling and ultimately cause gastric cancer.5 Another example of drug resistance can be seen in gammaproteobacterial, which expresses cytidine deaminase. This enzyme can completely metabolize gemcitabine, a chemotherapy drug utilized in the management of many cancers including bladder and breast cancer. Gemcitabine, when introduced to tumor microbiota, a high risk of drug resistance may occur and lead to tumor growth.  In a study using  a colon cancer mouse model, it was found that the presence of intratumoral bacteria, specifically gammaproteobacteria, was greatly linked to treatment resistance in tumors. Because this tumor type possessed the bacteria to modulate this tumor sensitivity to gemcitabine, a chemotherapy resistance was observed, with a lower concentration of gemcitabine in the body and increased adverse effects on the patient. These findings furthered ideas that microbiota plays a controversial role in cancer pathogenesis and development, as seen in its inflammation and resistance activities.

Microbiota as a Biomarker

Due to the difference in microbial population and quantity within tumor tissues as compared to normal cell tissues, the intratumoral microbiome can serve as a reliable diagnostic tool. For example, in the case of prostate cancer, it was found that the bacteria Propionibacterium acnes heavily resides in cancerous tissue and is even responsible for promoting a strong inflammatory response due to its activation of transcription and metalloproteinase pathways, such as STAT3 and COX2-prostaglandin. 7 Therefore, if a patient experiences strong inflammatory responses, it can be said there is a high likelihood for prostate cancer. The bacteria Fusobacterium nucleatum has been found in high amounts in the tissues of patients with colorectal cancer as well as in those with esophageal squamous cell carcinoma. In both types of cancer, these high levels of F. nucleatum have been associated with poor chemotherapeutic response and tumor recurrence.7 Due to its ability to upregulate cancer progression, metastases, and drug resistance, it can be advised that patients with high levels of this microorganism can receive antibiotic intervention, as there is a chance it greatly decreases neoadjuvant chemotherapy and significantly lowers survival rates in cancer patients. 

Conclusion

Intratumoral microorganisms continue to remain a puzzling aspect of cancer pathogenesis and other microbiomes in the body, such as gut microbiota, due to its paradoxical behavior of both suppressing tumor growth and promoting cancer development and inflammation. Though it is unclear yet why these microorganisms differ for each patient and how they can ultimately aid in cancer treatment, it is apparent that these agents are a helpful biomarker for a disease difficult to treat and diagnose.

References:

  1. National Cancer Institute. Cancer Statistics. National Cancer Institute. Published 2020. https://www.cancer.gov/about-cancer/understanding/statistics. Accessed February 20, 2024.
  2. Yang L, Li A, Wang Y, Zhang Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduction and Targeted Therapy. 2023;8(1). doi:https://doi.org/10.1038/s41392-022-01304-4
  3. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015;21(29):8787-8803. doi:10.3748/wjg.v21.i29.8787
  4. Si, W., Liang, H., Bugno, J., Xu, Q., Ding, X., Yang, K., Fu, Y., Weichselbaum, R. R., Zhao, X., & Wang, L. (2021). Lactobacillus rhamnosus GG induces cGAS/STING- dependent type I interferon and improves response to immune checkpoint blockade. Gut, gutjnl-2020-323426. https://doi.org/10.1136/gutjnl-2020-323426.
  5. Abreu, M., Peek Jr., R. (2017). Gastrointestinal Malignancy and the Microbiome. The Gut Microbiome and Disease, 146 (6), 1534-1546. https://doi.org/10.1053/j.gastro.2014.01.001
  6.  Khalaf K, Hana D, Chou JT-T, Singh C, Mackiewicz A and Kaczmarek M (2021)  Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Front. Immunol. 12:656364. doi: 10.3389/fimmu.2021.656364.
  7. Yamamura, K., Izumi, D., Raju Kandimalla, Fuminori Sonohara, Baba, Y., Yoshida, N., Yasuhiro Kodera, Baba, H., & Goel, A. (2019). Intratumoral Fusobacterium Nucleatum Levels Predict Therapeutic Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma. 25(20), 6170–6179. https://doi.org/10.1158/1078-0432.ccr-19-0318.
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