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CHaPter 14 The Microbiota in Immunity and Inflammation 215

to cancer, the host immune response needs to persist, rather Seminal discoveries have been made recently in delineating the
than being opposed by the host’s antiinflammatory arsenal. Thus pathways whereby the microbiota-primed immune system is
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similar nondiscriminatory immune regulatory mechanisms that essential for the success of common anticancer therapeutic agents.
are beneficial in curbing inflammation can impede antitumor Commensal bacteria support the potency of anti–IL-10R/CpG
immunity, thereby enabling tumor growth and eventual ODN treatment (a form of immunotherapy) as well as oxaliplatin
dissemination. 39 (a form of platinum salt chemotherapy) in treating colon car-
There are several immune-related mechanisms whereby cinoma by enhancing the production of myeloid-derived pro-
microbes directly impact the inflammation–cancer continuum. inflammatory cytokines and ROS, respectively. The efficacy of
Some pathogens can promote an inflammatory milieu that the alkylating drug cyclophosphamide (CTX) is reduced in
encourages tumor development, whereas others can directly germ-free mice or mice treated with vancomycin, which depletes
transform the eventual tumor-initiating cells. Oncogenic bacteria, gram-positive bacteria, as a result of diminished antitumor
including certain strains of Enterococcus faecalis, produce carci- adaptive immune responses. The microbiota is also critical for
nogenic reactive oxygen species (ROS) capable of inducing the antitumor effects of immune checkpoint inhibitors anti–
DNA-damaging compounds or can induce production of car- programmed death ligand 1 (PD-L1) and anti–cytotoxic T
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cinogenic compounds by activated immune cells. Inflammation- lymphocyte antigen-4 (CTLA-4). In human, anti–CTLA-4
induced cell turnover directly increases the likelihood of treatment induces mucosal damage and microbiota modification,
introducing mutations in replicating DNA. partly as a result of partial depletion of gut Tregs. The modified
microbiota and the consequent Th1-like immune response are
Microbiota–Immune System Interactions in Cancer critical for anti-CTLA_4 antitumor functions. In this study, the
Susceptibility and Development microbiota of patients treated with anti–CTLA-4 was enriched
Not surprisingly, animal models in which deletions of immune with bacterial species including Bacteroides thetaiotaomicron,
genes favor the emergence of a dysbiotic microbiota tend to Bacteroides fragilis, and Burkholderia cepacia. Transplantation
develop spontaneous nonremitting intestinal inflammation. These of germ-free mice with B. fragilis and B. cepacia partially rescued
include mice deficient in IL-10, Nod1, Nod2, Tbet, or Rag1. In the efficacy of anti–CTLA-4 and prevented the mucosal toxicity
several cases, microbiota reduction using antibiotics, rederivation of the antibody.
in an axenic (germ-free) environment, or colonization with the
microbiota derived from a wild-type animal is sufficient to
significantly inhibit the development of inflammation, as well THE SKIN MICROBIOTA AND THE
as the severity of cancer. Thus as a community, the microbiota IMMUNE SYSTEM
has the potential to drive both gut inflammation and the eventual
progression to cancer. Skin Microbes Maintain Barrier Integrity in the
The gut microbial community has also been implicated in Steady State
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modulating carcinogenesis outside the intestines in experimental With a surface area of approximately 1.8 m , skin is the largest
systems. Infection with Helicobacter hepaticus enhances mammary organ in the body. Skin functions as a physical barrier against
carcinoma in mice via mechanisms dependent on innate immune foreign agents (Chapter 19) and also participates in thermoregula-
activation and TNF production. In addition, TLR5 signaling tion. Unlike the warm, nutrient-rich intestinal tract, skin is cool,
promotes progression of sarcomas in mice deficient for the tumor dessicates, and is limited in available nutrients for microbial species.
suppressor p53, and in which the protooncogene Kras has been Thus skin is populated by microbial communities capable of
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activated. This disease phenotype can be abrogated by antibiotic- tolerating its diverse physiology (Fig. 14.6). The total bacterial
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mediated reduction in commensal bacterial load. content of healthy human skin averages about 1 million/cm , for
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In humans, approximately one of every six cancers develop upward of 10 total cells covering a single individual (or ≈1% of
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downstream of a pathogenic infection. Notable pathogen–cancer the number of bacterial cells per milliliter in the distal colon).
axes include Helicobacter pylori and gastric carcinoma, human The skin microbiota is generally acquired in concert with the
papillomavirus (HPV) and cervical cancer, and hepatitis B and colonization of other barrier surfaces in infancy. However, coin-
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C viruses and hepatocellular carcinoma. As with intestinal cident with the individual’s sexual maturation during adolescence,
inflammatory diseases, the composition of the fecal and mucosal his or her skin bacterial communities undergo a major shift. 45
microbiota in patients with colorectal cancer (CRC) is distinct Unlike the gut microbiota, skin commensals are dispensable
from that of healthy individuals. The differences between mucosal for the maturation of the immune compartment of the tissue.
bacterial populations present “on” and “off” the tumors in the However, their involvement in resistance to infection is clear. In
same patient suggest a role for site-specific bacterial community response to pathogen challenge, skin-resident microbes mount
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structure in disease development and/or production. More a robust innate immune response characterized by some of the
specifically, correlations have been made between CRC and the more primitive and evolutionarily conserved immune system
presence of colonic microbes, including enterotoxigenic Bacte- messengers—antimicrobial peptides (AMPs) including catheli-
roides fragilis, Fusobacterium nucleatum, Enterococcus faecalis, cidins and β defensins, components of the complement system,
and E. coli. Animal studies support a role for all these strains in and IL-1. Epithelial cells constitutively express some AMPs, which
Wnt signaling and myeloid cell activation of nuclear factor-κB can target a vast array of skin pathogens, including bacteria,
(NF-κB)–dependent inflammatory pathways. fungi, viruses, and parasites. Other AMPs are induced in a
microbiota-specific manner and are expressed secondary to
The Microbiota in Cancer Immunotherapy activation of the complement system. 45
Because of its ability to educate the immune system to be In addition to being part of the innate response to microbial
constantly poised to respond to challenge, the microbiota is now encroachment of skin, IL-1 stimulates robust adaptive immune
also recognized as an important ally in the fight against cancer. responses that are essential for containment of both pathogens