This web page was produced as an assignment for an undergraduate course at Davidson College.
Modern medicine is leaps and bounds more advanced and reliable than that of the past and continues to progress as time goes on. It seems as if each and every day new technology is invented and more effective treatments for diseases are being discovered. However, we have yet to find suitable, fully encompassing treatments for cancer, one of the deadliest diseases of all time, and all its variants. But that will perhaps be subject to change sometime in the near future. One promising step towards this future has been made in regard to the treatment of Melanoma. Melanoma is the deadliest form of skin cancer that occurs when pigment-producing cells called melanocytes mutate and begin to divide uncontrollably. If diagnosed in the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop significantly. (Davis et al., 2019) It is after the cancer metastasizes that additional treatment, such as immunotherapy, is needed. For Melanoma, this treatment is done through the use of anti-PD-1 medication. This medication is responsible for stopping the activation of PD-1 proteins which normally serve as off switches for the immune system so that it doesn’t target your healthy cells. By doing this the immune response is boosted against cancer cells. (Potter,2017) However, multiple studies have reported that response to anti–PD-1 treatment varied due to the gut microbiomes of cancer patients. In response to this, researchers of a study conducted in 2019 asked “How effective would a fecal microbiota transfer be at increasing anti-PD-1 treatment success?”.
To gain insight on the subject, researchers enrolled sixteen melanoma patients whose cancers were proven to be progressive and had not previously seen any response to anti-PD-1 treatment. All of these patients underwent continuous stool sampling to prevent the spread of infectious diseases. Similarly, all donor blood and stool samples were screened for various bacterial, fungal, and protozoan agents of disease. All patients were then given fecal matter transplants, each originating from a single, unique donor, as well as a dose of the anti-PD-1 medication Pembrolizumab. This treatment was followed by further treatments of Pembrolizumab every three weeks until their cancer progressed, or they could no longer tolerate the symptoms of the treatment. Researchers also conducted assessments using radiographs every twelve weeks for four cycles. Of the sixteen original patients, only fifteen were able to be evaluated to determine the results of the treatment as one patient experienced a rapid decline in health due to other circumstances.
To further understand the effects of the fecal microbiota transplant on the gut bacteria present in the patients, researchers performed shotgun metagenomic sequencing on the pre-transplant and post-transplant fecal matter of patients as well as that of their donors. This analysis showed that the gut bacteria of the transplant recipients did change significantly as long as antibiotics were not taken. The researchers noted that the gut microbacteria in patients that were responsive to anti-PD-1 treatment showed more variance. These patients also saw a change in their gut bacteria at a faster rate than the transplant patients that remained unresponsive to treatment, although this measurement was not statistically significant due to small sample size. Researchers also noted that the gut bacteria compositions of recipients that became responsive to treatment were more similar to the donors’ than the non-responsive recipients’ suggesting that these bacteria did in fact play a role in increasing the patients’ responsiveness to treatment.
To analyze the effects of fecal microbiota transplants on immune responses the researchers conducted single-cell RNA sequencing analysis on the patients’ tumor and peripheral blood mononuclear cells before and after the transplants. They found that responsive patients displayed higher percentages of CD56+CD8+ T cells 42 days after treatment than non-responsive patients. Responsive patients also exhibited lower percentages of naïve CD8+ T cells and higher percentages of terminally differentiated effector memory cells compared with non-responsive patients. These observations suggest that circulating CD8+ T cells are more activated and differentiated in responsive patients. All of these findings support the conclusion that fecal matter transplantation and anti–PD-1s counteract immunosuppression through altering CD8+ T cell activation near the tumors of responsive patients.
A final indicator of the effects of fecal microbiota transplants on melanoma patients was the change in cytokine and chemokine levels in responsive patients. To analyze these, researchers looked at the serum of both responsive and unresponsive patients and found that responsive patients’ levels of circulating cytokines and chemokines showed a prominent decrease while they remained stagnant in the serum of unresponsive patients. In particular, responsive patients saw a decrease in the frequency of IL-8, an immunosuppressive cytokine secreted by myeloid cells circulating in the bloodstream and inside tumors, that is tied to negative progress in anti-PD-1 treatment.
The findings shown in this paper indicate that a single fecal microbiota transplant along with PD-1 treatment can successfully colonize the gut of responsive patients and reprogram the tumor microenvironment to lose its resistance to anti–PD-1. The findings of this paper are extremely promising, but they need to be replicated in larger clinical trials to further prove their effectiveness. It would also be beneficial to further investigate the relationship between gut microbiota and various treatments for other cancers.
Khalil Miller is currently enrolled at Davidson College. Contact him at: khmiller@davidson.edu
references
Davis, Lauren E., et al. “Current State of Melanoma Diagnosis and Treatment.” Cancer Biology & Therapy, vol. 20, no. 11, 2019, pp. 1366–1379., doi:10.1080/15384047.2019.1640032.
Potter, Michelle. “Anti-PD-1: A Novel Immunotherapy.” Johns Hopkins Kimmel Cancer Center, 18 July 2017, www.hopkinsmedicine.org/kimmel_cancer_center/cancers_we_treat/melanoma/research/anti_pd_1.html.
Blacher, Eran, et al. “Potential Roles of Gut Microbiome and Metabolites in Modulating ALS in Mice.” Nature, vol. 572, no. 7770, 2019, pp. 474–480., doi:10.1038/s41586-019-1443-5.
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