Using the canine microbiome to bridge translation of cancer immunotherapy from pre-clinical murine models to human clinical trials

Abstract

The microbiome has clearly been established as a cutting-edge field in tumor immunology and immunotherapy. Growing evidence supports the role of the microbiome in immune surveillance, self-tolerance, and response to immune checkpoint inhibitors such as anti PD-L1 and CTLA-4 blockade (1–6). Moreover, recent studies including those using fecal microbial transplantation (FMT) have demonstrated that response to checkpoint immunotherapies may be conferred or eliminated through gut microbiome modulation (7, 8). Consequently, studies evaluating microbiota-host immune and metabolic interactions remain an area of high impact research. While observations in murine models have highlighted the importance of the microbiome in response to therapy, we lack sufficient understanding of the exact mechanisms underlying these interactions. Furthermore, mouse and human gut microbiome composition may be too dissimilar for discovery of all relevant gut microbial biomarkers. Multiple cancers in dogs, including lymphoma, high grade gliomas, melanomas and osteosarcoma (OSA) closely resemble their human analogues, particularly in regard to metastasis, disease recurrence and response to treatment. Importantly, dogs with these spontaneous cancers also have intact immune systems, suggesting that microbiome analyses in these subjects may provide high yield information, especially in the setting of novel immunotherapy regimens which are currently expanding rapidly in canine comparative oncology (9, 10). Additionally, as onco-microbiotic therapies are developed to modify gut microbiomes for maximal responsiveness, large animal models with intact immune systems will be useful for trialing interventions and monitoring adverse events. Together, pre-clinical mechanistic studies and large animal trials can help fully unlock the potential of the microbiome as a diagnostic and therapeutic target in cancer.

Comparative oncology using domesticated dogs and their microbiome

“…Also known as comparative oncology, it is an area that is quickly expanding to examine and compare the development of cancers across animal species ( 5 ). As mentioned above, murine models are used in translational research, including cancer; yet, mouse models of cancer in humans may not cover the vast and possibly complex gene network and interactions that may be responsible for or contribute to cancers in humans ( 6 ). Due to the genetic similarities between dogs and humans, pet dogs are, and are increasingly being considered, more suitable research models compared to mice for several diseases, including various types of cancers.…”

The human and animals’ malignant melanoma: comparative tumor models and the role of microbiome in dogs and humans

“…The colonization of both the canine and human gut microbiome increases in alpha diversity and decreases in beta diversity during the weaning period prior to stabilizing (0–3 years old in humans, 0–9 weeks in canines) [123]. It has been demonstrated that exposure to microbes during delivery, early diet, and antibiotic exposure have an impact on gut microbial development [120,123].…”

“…The colonization of both the canine and human gut microbiome increases in alpha diversity and decreases in beta diversity during the weaning period prior to stabilizing (0–3 years old in humans, 0–9 weeks in canines) [123]. It has been demonstrated that exposure to microbes during delivery, early diet, and antibiotic exposure have an impact on gut microbial development [120,123]. Early influences have a clinical impact: in children, for example, colonization with Clostridium difficile in the first months of life is related to an increased risk of atopic disorders such as asthma and eczema [124].…”

“…It has been consistently demonstrated that microbiomes of genetically unrelated co-habitants are more similar than those of relatives who do not cohabitate, and genetic ancestry does not predict compositional microbiome similarities [126,128]. Whereas environment is the primary influencer of microbiome composition, there seems to be heritability in canine and human gut microbiomes as well [123]. In a study with 400 human twin pairs raised in the same household monozygotic and dizygotic siblings were compared and, interestingly, monozygotic twins were revealed to have a more similar gut microbiota than their dizygotic counterparts [122].…”

“…In addition, it should be explored the oral/tumor microbiome in patients with COM. In humans, tumor-associated microbiomes have been identified in several cancers including one study in cutaneous melanomas [123]. There is only one study in COM; it identified bacteria ( Tannerella forsythia and Porphyromonas gingivalis ) that in humans are key for the development of periodontal disease and esophageal cancer [214].…”