Immunotherapies transformed cancer treatment by enhancing the immune system's ability to detect and kill cancer cells. However, immunotherapies have not been universally effective for all patients or for all cancer types. Emerging research suggests that the gut microbiome's influence on the immune response may play a significant role in this variation (1). While some bacteria contribute to immunotherapy success in some cancers, others inhibit the immune response that immunotherapies stimulate. 

A gentle nudge 

Gut bacteria’s influence isn't confined to the gut. For instance, in mice with melanoma, gut bacteria can amplify the effectiveness of immunotherapies. “I don’t think it’s a far stretch to say that a bug in your gut could modulate the development of a cancer in your gut. But if you say that a bug in your gut can help you fight melanoma on your skin, it just doesn’t make sense,” said Andrew Koh, a microbiologist at the University of Texas Southwestern Medical Center. 

Koh’s research team conducted a study to explore how healthy gut bacteria escape the gut and influence immunotherapy results in distant tumors such as those in the skin (2). The team focused on melanoma-afflicted mice receiving immune checkpoint inhibitor therapy, a form of immunotherapy that prods the immune system into attacking cancer cells. 

They found that the presence of skin tumors didn't prompt gut bacteria to migrate to the tumor site. However, immunotherapy treatment triggered inflammation in the mouse digestive system, leading bacteria to travel from the gut to nearby lymph nodes, similar to what happens during a bacterial infection. This bacterial movement increased the number and diameter of the lymph nodes' blood and lymphatic vessels, which then transported the bacteria selectively to skin tumors. They showed that the bacteria traveled exclusively to the tumor by injecting fluorescently labeled bacteria into the lymph nodes closest to the gut. They saw an increase in fluorescence only in the tumors of mice that received immunotherapy. This exciting discovery illustrates how gut bacteria can end up in tumors located elsewhere in the body. 

Bacteria are potent activators of the innate immune system, carrying pathogen-associated molecular patterns that dendritic cells recognize (3). At the tumor, the bacteria and dendritic cells interacted, which triggered an increase in the expression of major histocompatibility complex II and other costimulatory antigens on the surface of dendritic cells needed for T cell priming. Primed T cells expressed higher levels of interferon-γ, a cytokine that inhibits the growth of cancer cells. “Just like you need an adjuvant in a vaccine to get an optimal response, you may need an adjuvant to help prime T cells for any type of immunotherapy,” said Koh. 

Enterococcus faecalis  and Lactobacillus johnsonii  were the primary bacterial species making the journey from the gut to the lymph nodes and the tumor. Both are natural gut residents and associate with gut health (4,5). Other bacteria such as Akkermansia muciniphila  and Bacteroides thetaiotaomicron, which enhance the response to cancer immunotherapies, also migrated to the tumor (6,7).  

When bacteria are not friends

While bacteria's presence in skin tumors might be beneficial, this isn't a universal rule. The bacterial species Fusobacterium nucleatum, which is common in the oral cavity of healthy individuals, also thrives within tumors of the colon, where it arrives through the circulatory system during oral infections (8). Patients with high F. nucleatum levels within their tumors experience a robust immune reaction that paradoxically hampers immune cell infiltration into the tumor. 

“We’ve known for thousands of years that the immune system protects us from bacteria, so it's not surprising that immune cells inside the tumor react to them,” said Jorge Galeano Niño, a cancer immunologist at the Fred Hutchinson Cancer Center. “However, that response is not always beneficial in cancer because it impairs the T cell response that clears cancer cells.” 

Galeano Niño assessed the effect of F. nucleatum on colorectal and oral cancer progression in a 2022 study published in Nature (9). He found that the macrophages and neutrophils that responded to bacteria produced anti-inflammatory molecules such as arginase and interleukin-10, which prevented T cells from entering the tumor. “We believe this is the reason cancers are refractory to immunotherapies,” he said. 

Bacterial cells also directly contribute to chemotherapy resistance and possibly metastasis. Galeano Niño found that some tumor bacteria reduced the ability of cancer cells to proliferate. While this might initially sound beneficial, it would make the tumor less sensitive to chemotherapies since they target cells that are actively dividing. This might also result in cancer relapse if chemotherapy-resistant areas of the tumor get reactivated (10). Moreover, conditions that allow cancer cells to stop dividing could also promote metastasis by encouraging cell migration (11). 

Antibiotic assistance

If bacteria drive colorectal and oral cancer progression, a reasonable strategy might be to use antibiotics to make the tumors sensitive to immunotherapies. The antibiotic metronidazole can reduce Fusobacterium levels and tumor growth in mice with colon cancer (12). However, applying a similar approach in humans won’t be as simple given that bacteria prefer hard to reach areas of the tumor with poor circulation, which would make antibiotic delivery challenging. 

In the case of melanoma, Koh’s group found that giving antibiotics to the melanoma-bearing mice receiving immunotherapy decreased the number of bacteria that moved from the gut. This meant fewer bacteria entered the lymph nodes and the tumor itself, which caused a weaker activation of the immune system against cancer cells. 

Whether reducing or eliminating bacteria will be harmful or beneficial for the outcome of immunotherapy treatment might depend on the bacteria type that the tumor harbors. According to Galeano’s data, Fusobacterium, Bacteroides, and Triponema bacteria trigger a potent inflammatory response that neutralizes T cells, while other bacteria might not interfere with T cell responses. The outcome might also depend on the tumor. “Bacteria are present in 33 types of solid tumors,” said Galeano Niño, “And it seems that the microbiome is different in every cancer type.” 

In the end, each tumor might require a unique approach tailored to its specific microbiome profile. Understanding and leveraging these microbial differences could pave the way for breakthroughs in patient-specific treatments and offer new hope in the ongoing fight against cancer. 

References 

1. Lu, Y., Yuan, X., Wang, M. et al. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J Hematol Oncol  15, 47 (2022). 
2. Choi, Y., Lichterman, J.N., & Coughlin, L.A. et al. Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Science immunology  8(81), (2023). 
3. Hobohm, U., Stanford, J. L., & Grange, J. M. Pathogen-associated molecular pattern in cancer immunotherapy. Crit Rev Immunol  28, 95-107 (2008). 
4. Krawczyk, B., Wityk, P., Galęcka, M., & Michalik, M. The many faces of Enterococcus spp.- commensal, probiotic and opportunistic pathogen. Microorganisms  9, 1900 (2021). 
5. Dempsey, E. & Corr, S. C. Lactobacillus spp. for gastrointestinal health: current and future perspectives. Front Immunol  13, 840245 (2022). 
6. Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., & Alou, M. T. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science  359, 91-97 (2018). 
7. Huang, J., Zheng, X., Kang, W., Hao, H., & Mao, Y. et al. Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer. Front Immunol  13, 874922 (2022). 
8. Abed, J., Maalouf, N., Manson, A. L., Earl, A. M., & Parhi, L. et al. Colon cancer-associated Fusobacterium nucleatum may originate from the oral cavity and reach colon tumors via the circulatory system. Front Cell Infect Microbiol  10, 400 (2020). 
9. Galeano Niño, J.L., Wu, H., & LaCourse, K.D. et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature  611, 810–817 (2022). 
10. Mitola, G., Falvo, P., & Bertolini, F. New insight to overcome tumor resistance: an overview from cellular to clinical therapies. Life  11, 1131 (2021). 
11. Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A., & Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther  5, 28 (2020). 
12. Bullman, S., Pedamallu, C. S., Sicinska, E., Clancy, T. E., & Zhang, X. et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science  358, 1443-1448 (2017).