As mentioned in our discussion of infectious agents (in our last Blog #28), it is estimated that individual microbial pathogens contribute to cancer development in approximately 20% of total cases. Among these pathogens, genetic mutations are the main drivers of tumor initiation, with contributions from secondary risk factors like diet, age, lifestyle factors, microbes, etc. However, we now know that the microbiome can regulate the effects of tumor-driven mutations and progression through direct effects on the tumor cells and indirectly through manipulation of the immune system. The microbiota may affect tumor immunity by regulating the host immune system and the tumor’s microenvironment.
Some bacteria help fight tumors by activating immunity, while others mediate immunosuppression to help cancer cells escape from the immune system. The composition of the intestinal microbiota that is sensitive to treatment or prone to adverse reactions can be used as biomarkers to predict the prognosis of immunotherapy and may also assist immunotherapies. The role of the microbiota in regulating not only gut but also systemic immune responses is being studied as to the impact on cancer immunotherapies, particularly with agents targeting the immunologic checkpoint inhibitors PD-1 and CTLA-4 (discussed previously under monoclonal antibodies, checkpoint inhibitors in Blog #21, below under “sex-specific clusters”, and later under “combination strategies” in Blog #34).
Efforts are underway to establish the role of each microbe or group of microbes in different kinds of cancers. Physiological responses to immunotherapy, antibiotics, radiation, and chemotherapy in microbes need to be explored. There are numerous immunotherapy strategies being implemented
to manipulate multiple immune pathways and molecules. These strategies and increased understanding of the gut microbiomes in immunotherapy has provided a significant impact on clinical therapeutics. The immunologic status of the host, tumor invasion status and biology of malignancies are determining factors for individualized therapy. Additional research on the microbiome will undoubtedly lead to the earlier treatment of various cancers.
MicroRNAs (miRNA) are small noncoding RNA molecules that possess enormous regulatory powers. They play key roles in almost all physiological pathways, and more so for our discussion, in the pathogenesis of autoimmune diseases and cancers. Their genomic distribution as previously described in Blog #12 demonstrates their highest density of sequences on the X chromosome. It is estimated that miRNA regulates up to 50% of all protein-coding genes. Based on “lyonization” or XCI (X chromosome inactivation) described back in Blog #12, this prodigious, complex embryologic (and evolutionary) genomic process equips females with greater miRNA machinery than males - “for better and for worse” (pardon the pun).
In previous blogs, we have already demonstrated some of the multiple ways that molecular biology
contributes to the female predilection for autoimmune diseases as well as cancer risks for both males and females. Now let’s consider some additional examples to accentuate the profound influences (and paradoxes) the miRNA and X chromosome amalgam produce. The female immune system is flexible in its ability to counteract infections and noninfectious diseases, including cancers. This advantage, however, is yet again a paradox of the immune system in that it can result in increased susceptibility to developing autoimmune diseases. Meanwhile, a significant number of X-linked miRNAs (e.g., miR-221, 222, 98, 532, and more) help in regulating the immune system, but also have oncogenic potential. To add to this complex puzzle, there exist miRNA-dependent, sex-specific clusters like the PD-1/PD-L1 pathway (described below under “combination therapies”) that can both regulate immune responses and provide T-cell cancer immunosurveillance against tumors. Relative to breast cancers, the most common cancer in women, 2 circulating X-linked miRNAs have been identified (miR-106a-363 and miR-532-502) as promising diagnostic biomarkers. Continued research will lead to the identification of new biomarkers for additional forms of cancer.
Discussion Questions:
We know that the microbiome can regulate the effects of tumor-driven mutations and progression. Can you explain how the microbiota accomplish this effect?
X-linked miRNAs help in regulating the immune system, but also have oncogenic potential. What other miRNA-dependent pathway can both regulate immune responses and provide T-cell cancer immunosurveillance against tumors?
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