Immunooncology is a new field of science focusing on the activation mechanisms of the immune system, which has natural anti-cancer defense mechanisms. The development of many neoplastic diseases depends on the fact that immune system loses control over cancer. Modern anti-cancer immunotherapies enhance the immune response by targeting it directly at cancer cells. Treatment of neoplasms shows different effectiveness and toxicity, and the sooner the treatment is started, the better the patient’s prognosis.
The most frequently used method of cancer immunotherapy in clinical practice is the use of monoclonal antibodies directed against neoplastic antigens and which may enhance the host’s immune response or inhibit tumor growth by blocking cancer growth factors.
Gut microbiome and the immune system
The development of the microbiome goes hand in hand with the formation of cells of the immune system, therefore they are considered to be interdependent processes. It has been shown that the immune system is constantly stimulated by compounds of intestinal microorganisms, such as lipopolysaccharides (LPS), flagellin and unmethylated CpG motifs (bacterial DNA fragments recognized by cells of the immune system). They shape the differentiation of T lymphocytes into regulatory cells (Treg) or the Th1, Th2, and Th17 subpopulation. Treg lymphocytes play a special role as they are able to inhibit the differentiation of Th cells, eosinophils, basophils, mast cells and the production of immunoglobulin E. Properly maintained balance between subpopulations of T lymphocytes may protect against the occurrence of chronic autoimmune and allergic diseases. Considering the role of microbiota in lymphocyte differentiation, it is believed that disturbances in its composition may predispose to the occurrence of these diseases. This is confirmed by studies carried out on sterile (GF germ-free) mice, where it has been shown that the presence of intestinal microbiota is necessary for Treg differentiation, and that some bacterial strains can directly influence their activation.
The importance of microorganisms in the oncology
Viruses such as EBV and HPV contain genes that influence cell cycles and their checkpoints, and additionally inhibit the activity of tumor suppressors, and are therefore believed to play a role in initiating the neoplastic process. Bacteria participate in the development of inflammation and contribute to the production of reactive oxygen species, inducing oncogenesis. The role of bacteria is unclear as they can also influence host genes and thus regulate cell cycles, apoptosis and other tumor development processes. Helicobacter pylori can induce carcinogenesis on the background of the resulting inflammation, and the persistent inflammation predisposes to uncontrolled cell proliferation. In recent years, scientists have linked the gut microbiota and immune profiles with interindividual variability in response to treatment. The observed Th17 cell growth in H. pylori-associated gastric cancer and enterotoxigenic Bacteroides fragilis (ETBF) – related colon cancer led scientists to suspect that certain bacterial taxa had oncogenic potential.
Using Fusobacterium nucleatum as an example, it has been shown to induce inflammation and upregulate host oncogenes. Interactions between its virulence factor FadA and E-cadherin present on epithelial cells, in particular colon cancer cells, have been observed. As a result, bacterial endocytosis occurs, followed by the activation of NF-κB, which increases the production of inflammatory cytokines. The accumulation of many processes leads to increased cell proliferation and cell cycle checkpoints are omitted. Fusobacterium nucleatum influences carcinogenesis in many ways, and inhibiting only one mechanism may be insufficient in the treatment of cancer.
It has been observed that the presence of some bacterial strains is higher during tumor development, and this would suggest the presence of local neoplastic microflora, which may translate into therapy induction and influence the interaction between bacteria and the immune system. Moreover, the presence of a long-term state of dysbiosis has been correlated with the higher risk of developing cancer.
Gut microbiota transplantation is a procedure that restores the balance in the composition of the gut bacteria. FMT is primarily used to treat recurrent C.difficile infections, but scientists are currently trying to prove the effectiveness of the FMT procedure in many others indications. For example, immunodeficient patients, including those who have undergone bone marrow transplants, may benefit from this form of treatment. Frequently, before the transplantation of bone marrow cells for prophylactic purposes, antibiotics with a broad spectrum of activity are used, which lead to the depletion of microorganisms. It has been proven that the mortality rate is higher in patients with reduced bacterial diversity after HSCT (Hematopoietic stem cell transplantation) compared to patients who were not diagnosed with dysbiosis. A real scientific revolution is the confirmation that without the proper composition of the intestinal microbiota, the most modern immuno-oncological therapies, such as the so-called ICI (Immune Checkpoint Inhibitors) are not working. The use of FMT in patients with disseminated melanoma and other neoplasms treated with ICI resulted in some patients being sensitized to this treatment and even complete remission of neoplasms. More information here.
Schwartz DJ, Rebeck ON, Dantas G. Complex interactions between the microbiome and cancer immune therapy. Crit Rev Clin Lab Sci. 2019 Dec;56(8):567-585. doi: 10.1080/10408363.2019.1660303. Epub 2019 Sep 17. PMID: 31526274; PMCID: PMC6776419.
Jasiński M, Biliński J, Basak GW. The Role of the Crosstalk Between Gut Microbiota and Immune Cells in the Pathogenesis and Treatment of Multiple Myeloma. Front Immunol. 2022 Mar 31;13:853540. doi: 10.3389/fimmu.2022.853540. PMID: 35432306; PMCID: PMC9009288.