Mechanisms and microbial influences on CTLA-4 and PD-1-based immunotherapy in the treatment of cancer: a narrative review

The relationship between gastrointestinal (GI) bacteria and the response to anti-CTLA-4 and anti-PD-1 immunotherapy in the treatment of cancer can potentially be enhanced to allow patients to maximally respond to these treatments. Insight into the complex interaction between gut microbiota and the human adaptive immune system will help guide future immunotherapeutic cancer treatments to allow a more robust clinical response and fewer adverse effects in patients requiring these drugs. This review highlights these interactions as well as the potential for the creation of “oncomicrobiotics” that would selectively tailor one’s GI bacteria to maximally respond to anti-CTLA-4 and anti-PD-1 treatments will fewer adverse effects.

CTLA-4 is an antigen on the surface of T cells which, upon stimulation, leads to inhibition of activated T cells to terminate the immune response. However, many types of tumor cells can upregulate CTLA-4 in the tumor microenvironment, allowing these cells to evade targeting and destruction by the body’s immune system by prematurely inhibiting T cells. Increased representation of Bacteroides fragilis, Burkholderia cepacia and the Faecalibacterium genus in the GI tract of patients receiving CTLA-4-based immunotherapy led to a stronger therapeutic effect while minimizing adverse side effects such as colitis. In addition, by introducing bacteria involved in vitamin B and polyamine transport to the GI tracts of patients treated with anti-CTLA-4 drugs led to increased resistance to colitis while maintaining therapeutic efficacy. PD-1 is another molecule upregulated in many tumor microenvironments which acts in a similar manner to CTLA-4 to tone down the anti-neoplastic actions of T cells. Antibodies to PD-1 have shown promise to help allow the body’s natural immune response to appropriately target and destroy tumor cells. The presence of Bifidobacterium breve and longum, Akkermansia muciniphila and Faecalibacterium prausnitzii in the GI tracts of cancer patients has the potential to create a more robust immune response to anti-PD-1 drugs and prolonged survival. The development of “oncomicrobiotics” has the potential to help tailor one’s gut microbiota to allow patients to maximally respond to immunotherapy without sacrificing increases in toxicity. These oncomicrobiotics may possibly include antibiotics, probiotics, postbiotics and/or prebiotics. However, many challenges lie ahead in the creation of oncomicrobiotics.

The creation of oncomicrobiotics may allow many patients receiving anti-CTLA-4 and PD-1 immunotherapy to experience prolonged survival and a better quality of life.