Immunotherapy in Pancreatic Cancer: Does Bacteria hold the answer?

Manisit Das

Your gut is crawling with bacteria, despite your devoted hygiene practices. Disgusting for your sophisticated self, isn’t it? Surprising as it is, over the course of evolution our bodies tolerated the microbial communities in our body, even cherished them. Hundreds of thousands of bacteria and other microorganisms call us home and play a key role in maintaining our health, often doing more good than bad.

As we began our journey of sharing the story of cancer at OncoBites, we shared with you the fascinating world of gut microbes. Recently, there has been a significant accumulation of scientific literature on how the microbes in our gut can affect tumor progression and modulate cancer therapy.

Anatomy of the Pancreas

The pancreas is a gland located behind the stomach that secretes enzymes that aid digestion of food in the small intestine. For a while, not much was known about the role of microbes in pancreatic cancer. Scientists have yet to find a major breakthrough against this killer cancer with a five-year survival of only 8%. Pancreatic tumors are difficult to treat, and we have not yet developed drugs against the major drivers of the disease. Does bacteria in the gut or the tumor hold a clue to finding a breakthrough? Accumulating evidence suggests that the composition of gut bacteria and use of antibiotics may affect how a patient will respond to cancer therapies.

The functional relationship between gut bacteria and treatment outcomes in pancreatic cancer has only been recognized in recent years. Gemcitabine is one of the standard chemotherapy drugs used to treat pancreatic cancer. In a recent study using mouse models of colon cancer, it was found that bacteria belonging to the class of Gammaproteobacteria in the tumor can convert gemcitabine to an inactive form. The authors suspected that since gemcitabine is commonly used to treat pancreatic cancer, the presence of this bacteria in the tumor may contribute to resistance against the drug. To assess this hypothesis, they analyzed tissue samples from about hundred patients with Pancreatic Ductal Adenocarcinoma, a form of cancer that starts in the cells of the pancreatic ducts. They found that about 4 out of every 5 patients have the bacteria present in their tumor. While a hundred patients is not a very big number, it definitely raises some questions about how bacteria can affect the natural course of the disease and treatment.

Another study was published this year in April, which highlights the influence of bacteria on antitumor immunity. This is a surreal idea that we started with at the inception of our blog (From bacteria in your gut to cancer in your skin, everything is connected). The researchers behind this work found that there were more bacteria in both mice and human pancreatic cancer patients compared to their healthy counterparts. To know more about the journey of the gut microbes through the back allies of our body, they fed the mice bacteria labeled with fluorescent tags and monitored them, in the process identifying the tagged bacteria in the pancreas. This is an important result, as it tells us that bacteria can potentially migrate from the gut to pancreas and directly influence the environment around the tumor.

Pre-cancerous pancreatic tissue in mice

Once the researchers identified the increase of bacteria in the pancreatic tumors over healthy pancreas they were curious about the possible consequences of clearing the bacteria by antibiotics. They found that antibiotic treatment can change how immune cells respond to the pancreatic tumor. The microbes in the gut and the pancreas promote immune suppression by allowing the enrichment of the tumor environment with suppressive immune cells that blunt the activity of the antitumor immune cells. After antibiotic treatment,  T cells, that help to recognize and clear pathogens, were increased in the tumor. In addition to recognizing and killing foreign cells like bacteria, these T cells can also recognize and clear our own cells when they go awry and become cancerous. Importantly, the authors also identified a decrease in the proportion of the suppressive immune cells that the cancer cells use to their advantage to defend themselves against the killer immune cells. The change in the immune cell populations also affected tumor progression in the mice: tumor weight was reduced more than 50% when compared to normal animals.

In a rather gut-wrenching experiment, I hope not literally, the researchers next transferred feces from pancreatic tumor-bearing animals to animals previously treated with antibiotics. This kind of fecal microbiota transplant is increasingly gaining traction in many digestive and autoimmune disorders. The typical purpose of these transplants is to replace good bacteria that are lost, usually by antibiotics treatment. In cancer therapy, the focus is to colonize patients with targeted species of microbes to favor a positive outcome. However, in this case, the goal of the researchers was to validate the effect of the gut microbiome on immunotherapy in pancreatic cancer. The fecal transfer reversed the tumor shrinkage and nullified the effect of antibiotic depletion. This further reinforces that the microbes in the gut indeed play a role in the progression of the pancreatic tumor.

The researchers also tested the combination of antibiotic depletion and immune checkpoint inhibitor therapy. Checkpoint inhibitor therapy relies on releasing the brakes on the T cells and empowering them to fight against the tumor. They found that the effect of antibiotic-mediated bacterial depletion further augments the therapeutic effect of immune checkpoint inhibitors. What this essentially means is when the animals received checkpoint inhibitor drugs after treatment with antibiotics, the tumors were smaller than when treated with checkpoint inhibitors alone. This is one of the unique highlights of this current study. Sara had shared in her earlier post how the presence of certain bacteria can favor a positive outcome from checkpoint inhibitor therapy. The current results in pancreatic cancer stand in contrast to that. This also reminds us how every cancer is different and depending on the distinct cluster of changes and composition of microbiota in each cancer, it can very distinctly affect treatment!

The fight against pancreatic cancer has united researchers all over the world. We got our hopes up with the latest advances in immunotherapy. But so far, we haven’t had much success. Use of antibiotics to tweak the microbial communities to improve the outcome of immunotherapy is a unique strategy. However, we are yet to know what are the major communities of microbes that may positively and negatively affect the treatment outcomes in a larger cohort of patients. We hope that future research will shed more light if microbes can be used clinically to convert the immunotherapy resistant pancreatic tumors to responsive cancers.

Works Discussed

Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., . . . Miller, G. (2018). The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discovery, 8(4), 403-416. doi: 10.1158/2159-8290.CD-17-1134

Riquelme, E., Maitra, A., & McAllister, F. (2018). Immunotherapy for Pancreatic Cancer: More Than Just a Gut Feeling. Cancer Discovery, 8(4), 386-388. doi: 10.1158/2159-8290.CD-18-0123

Image Credits 

The Pancreas Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436

Pre-cancerous pancreatic tissue in mice, NIH Image Gallery

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