Rachel Lim ‘29
In 1863, German physician Rudolf Virchow, “the father of modern pathology,” observed the increased presence of white blood cells in abnormal tissue growth and was the first to propose the relationship between immune function and cancer. From the 1890s to the 1930s, doctors observed that some bacterial infections caused tumors to shrink. These findings motivated American surgeon William B. Coley and his colleagues to explore whether boosting the body’s immune response could be used to combat cancer. A century after Coley and others pioneered the field of cancer immunotherapy, it has only recently begun to advance rapidly, revolutionizing cancer treatment. Additionally, recent studies have shown that some tiny organisms, particularly bacteria living in our gut, may hold one of the keys to immunotherapy’s success.
The adaptive immune system is the branch of our immune system that recognizes, memorizes, and mounts targeted attacks to specific threats. During an immune attack on cancer, many different cells work together to identify cancer cells and release chemicals to kill them, as shown in Figure 1. In one type of adaptive immune response called a cell-mediated immune response, antigen-presenting cells (APCs) first take in antigens, which are abnormal molecules found on the surfaces of cancer cells that trigger immune responses. In the lymph nodes, APCs prime T-cells to identify and specifically kill cancer cells presenting these same antigens. Once activated, primed T-cells travel to the tumor, recognize the antigen on cancer cells, bind to the cells through specific receptor pathways, and release chemicals such as cytokines and granzymes that direct the immune response and kill cancer cells.
However, cancer cells can avoid being destroyed by exploiting regulatory mechanisms that dampen the immune response. One such mechanism involves surface proteins binding to specific receptors on attacking T-cells to “calm” them down. This is one of the obstacles cancer immunotherapy aims to overcome in helping immune cells fight cancer. An example of a pathway that cancer cells use to block attacking T-cells involves programmed cell death protein 1 (PD-1), a receptor expressed by T-cells, and its binding molecule, PD-L1, which can be expressed by cancer cells as well as immune cells. When PD-L1 binds to PD-1, it sends T-cells a “stop” signal, preventing their immune attack. To combat this, researchers have developed antibodies called aPD-1 and aPD-L1 that are supposed to block the PD-1/PD-L1 pathway and allow the anti-tumor immune response to continue; they are used in anti-PD1 and anti-PD-L1 therapy (see Figure 2). These antibodies, called checkpoint inhibitors, have been proven to improve anti-tumor immune responses (Ribas & Wolchok, 2018). Although highly promising, immune checkpoint inhibitor treatments are effective only for certain cancer types, and responses vary widely; as of 2023, response rates to aPD-1 and aPD-L1 therapy ranged from 13% to 69% depending on tumor type (Ribas & Wolchok, 2018).
Understanding the role of gut bacteria in immune checkpoints could reduce this response variability and improve patient outcomes. In 2015, it was found that certain gut bacteria promoted anti-tumor responses in mice for both aPD-L1 therapy (Sivan et al., 2015) and in CTLA-4 blockade, another immunotherapy treatment (Vetizou et al., 2015). In 2017 and 2018, several studies found that patients who responded to immunotherapy had different gut microbiomes than non-responders (Gopalakrishnan et al., 2017; Matson et al., 2018; Routy et al., 2018). After this evidence of bacteria strengthening immunotherapy responses was discovered, clinical trials in 2020 and 2021 proved fecal microbiota transplants (FMTs), which transfer gut bacteria from responder patients into nonresponder patients, to be successful in helping some non-responders overcome immunotherapy resistance (Davar et al., 2021; Baruch et al., 2020).
In 2023, Joon Seok Park and Francesca S. Gazzaniga co-authored a study published in Nature that identified a specific pathway by which some bacteria can promote anti-tumor immunity (Park & Gazzaniga, 2023). The study revealed that gut bacteria can improve anti-tumor responses in mice by inhibiting the interactions between PD-L2 (a protein similar to PD-L1) and one of its binding partners, repulsive guidance molecule b (RGMb). It also identified bacteria species Coprobacillus cateniformis as one among others that are able to promote responses to a PD-1 therapy and decrease PD-L2 expression on dendritic cells, a type of antigen-presenting cell. As PD-L2 expression is reduced, T-cells are better able to follow through with their attacks on tumor cells. Interestingly, dendritic cells cultured with broken-down C. cateniformis cells were able to elicit strong anti-tumor responses, suggesting that something on the surface of C. cateniformis cells is involved in strengthened reception to immunotherapy. These insights were a substantial step towards bringing the role of gut bacteria in immunotherapy to clinical relevance, as the identification of the specific mechanisms and molecules involved would circumvent the variability of FMTs and allow for medicines to be developed and given to patients undergoing immunotherapy.
Dr. Gazzaniga’s lab at Massachusetts General Hospital and Harvard Medical School continues the search for other potentially beneficial bacteria species and works to elucidate the specific mechanisms and molecules that allow for enhanced anti-tumor responses to immunotherapy. Among other projects, they perform DNA extraction, purification, and sequencing to identify beneficial bacteria from samples provided by patients who were responsive to immunotherapy, and they test the impacts of bacteria in reducing tumor sizes for different cancer cell lines implanted in mice. As a mere high schooler interning there over two summers, learning how to work with mice, plate bacteria, and culture cancer cell lines and dendritic cells was a little daunting at first. But with the privilege of working with amazingly patient and knowledgeable mentors, I was able to immerse myself in learning about immunology, bacteria, very cool laboratory techniques, and the fun of research. Being able to contribute at least a little to such fascinating research is something I will always be very grateful for, and it’s made me excited to get back into laboratory work in my time at Princeton and beyond.
The impacts of the gut microbiome on cancer immunotherapy responses have immense implications in the wellbeing of many cancer patients who have been unresponsive to or unable to receive chemotherapy and immunotherapy treatments. As the Gazzaniga Lab and other molecular pathology labs around the world continue to search for ways to translate these bacterial benefits into clinical practice, we can be sure to watch with bated breath for a potential breakthrough that may provide both hope and firepower in the fight against cancer.
FIGURE 1: The cycle of an immune attack on cancer in the body. (Demaria et al., 2019)
FIGURE 2: The PD-L1 and PD-1 pathway between T cells and tumor cells is able to be blocked by anti-PD-L1 and anti-PD-1 checkpoint inhibitors to sustain the anti-tumor immune response. (National Cancer Institute)
Rachel Lim is a staff writer at The Princeton Medical Review. She can be reached at rl5352@princeton.edu.
References
Balkwill, F., & Mantovani, A. (2001). Inflammation and cancer: back to Virchow? The Lancet, 357(9255), 539–545. https://doi.org/10.1016/s0140-6736(00)04046-0
Baruch, E. N., Youngster, I., Ben-Betzalel, G., Ortenberg, R., Lahat, A., Katz, L., Adler, K., Dick-Necula, D., Raskin, S., Bloch, N., Rotin, D., Anafi, L., Avivi, C., Melnichenko, J., Steinberg-Silman, Y., Mamtani, R., Harati, H., Asher, N., Shapira-Frommer, R., & Brosh-Nissimov, T. (2020). Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science, 371(6529), 602–609. https://doi.org/10.1126/science.abb5920
Davar, D., Dzutsev, A. K., McCulloch, J. A., Rodrigues, R. R., Chauvin, J.-M., Morrison, R. M., Deblasio, R. N., Menna, C., Ding, Q., Pagliano, O., Zidi, B., Zhang, S., Badger, J. H., Vetizou, M., Cole, A. M., Fernandes, M. R., Prescott, S., Costa, R. G. F., Balaji, A. K., & Morgun, A. (2021). Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients. Science, 371(6529), 595–602. https://doi.org/10.1126/science.abf3363
Demaria, O., Cornen, S., Daëron, M., Morel, Y., Medzhitov, R., & Vivier, E. (2019). Harnessing innate immunity in cancer therapy. Nature, 574(7776), 45–56. https://doi.org/10.1038/s41586-019-1593-5
Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., Cogdill, A. P., Zhao, L., Hudgens, C. W., Hutchinson, D. S., Manzo, T., Petaccia de Macedo, M., Cotechini, T., Kumar, T., Chen, W. S., & Reddy, S. M. (2017). Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science, 359(6371), 97–103. https://doi.org/10.1126/science.aan4236
Han, Y., Liu, D., & Li, L. (2020). PD-1/PD-L1 pathway: current researches in cancer. American Journal of Cancer Research, 10(3), 727. https://pmc.ncbi.nlm.nih.gov/articles/PMC7136921/
Matson, V., Fessler, J., Bao, R., Chongsuwat, T., Zha, Y., Alegre, M.-L., Luke, J. J., & Gajewski, T. F. (2018). The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science, 359(6371), 104–108. https://doi.org/10.1126/science.aao3290
Munir, M., Cheema, A. Y., Ogedegbe, O. J., Aslam, M. F., & Kim, S. (2024). William Coley: The Pioneer and the Father of Immunotherapy. Cureus, 16(9), e69113. https://doi.org/10.7759/cureus.69113
National Cancer Institute. (2022, April 7). Immune Checkpoint Inhibitors. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors
Park, J. S., Gazzaniga, F. S., Wu, M., Luthens, A. K., Gillis, J., Zheng, W., LaFleur, M. W., Johnson, S. B., Morad, G., Park, E. M., Zhou, Y., Watowich, S. S., Wargo, J. A., Freeman, G. J., Kasper, D. L., & Sharpe, A. H. (2023). Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance. Nature, 1–9. https://doi.org/10.1038/s41586-023-06026-3
Ribas, A., & Wolchok, J. D. (2018). Cancer immunotherapy using checkpoint blockade. Science, 359(6382), 1350–1355. https://doi.org/10.1126/science.aar4060
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., Fidelle, M., Flament, C., Poirier-Colame, V., Opolon, P., Klein, C., Iribarren, K., Mondragón, L., Jacquelot, N., Qu, B., & Ferrere, G. (2018). Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.), 359(6371), 91–97. https://doi.org/10.1126/science.aan3706
Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-Michaels, K., Earley, Z. M., Benyamin, F. W., Man Lei, Y., Jabri, B., Alegre, M.-L. ., Chang, E. B., & Gajewski, T. F. (2015). Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science, 350(6264), 1084–1089. https://doi.org/10.1126/science.aac4255
Vetizou, M., Pitt, J. M., Daillere, R., Lepage, P., Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy, B., Roberti, M. P., Duong, C. P. M., Poirier-Colame, V., Roux, A., Becharef, S., Formenti, S., Golden, E., Cording, S., Eberl, G., Schlitzer, A., Ginhoux, F., & Mani, S. (2015). Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 350(6264), 1079–1084. https://doi.org/10.1126/science.aad1329
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