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Procaccianti et al. Microbiome Res Rep 2023;2:24 https://dx.doi.org/10.20517/mrr.2023.23 Page 5 of 12

advantages, namely increased objective response rates and overall survival. Furthermore, the intestinal
residence of Akkermansia was found to be a proxy for the richness of the gut ecosystem, which is generally
related to more favorable outcomes. Finally, two studies in melanoma patients have identified other
commensal microbes potentiating the antitumor effects of PD-1 blockade in responders [45,46] . Notably,
responders exhibited greater interindividual diversity (which suggests retention of one’s GM fingerprint or
uniqueness) and higher levels of Faecalibacterium and other health-associated Ruminococcaceae members,
which were involved in enhanced antigen presentation and T cell function in the tumor
[45]
microenvironment . For a list of bacteria other than Bifidobacterium that have been suggested to date to
play a role in the success (or failure) of immunochemotherapy, please consult the relevant literature (e.g.,
[61]
Table 1 from Gupta et al. 2021 , including pathogenic and non-pathogenic bacteria mediating cancer
[62]
immunotherapy, and Tang et al. 2022 , who also discussed engineered bacteria with enhanced tumor
tropism, significant immunomodulation and improved safety profile, for enhanced therapeutic outcomes in
different cancer models).

BIFIDOBACTERIUM AND THE IMMUNOCHEMOTHERAPY LANDSCAPE
In this context, Bifidobacterium deserves special attention as it has been directly involved in the response to
immunochemotherapy [63,64] . For example, in 2015, Sivan et al. compared antitumor T lymphocyte responses
[65]
in murine models purchased from two different facilities , namely Jackson Laboratory (JAX) and Taconic
Farms (TAC) mice. Compared to TAC mice, JAX mice developed adequate antitumor immunity.
Interestingly, the mice also differed in GM composition, with Bifidobacterium being overabundant in JAX
mice. After induction of melanoma in both murine models, JAX mice exhibited reduced tumor cell growth
and enhanced T cell-mediated immune surveillance. Overabundance of Bifidobacterium, particularly species
B. breve, B. longum and B. adolescentis, was positively associated with the antitumor response mediated by
activation of T cell effectors. Furthermore, oral administration of B. breve and B. longum to mice with
Bifidobacterium depletion was sufficient to reduce natural melanoma growth alone and, in association with
immunotherapy (anti-PD-L1), to restore specific antitumor T cell responses and almost abolish tumor
outgrowth. Increased dendritic cell function leading to T cell activation in the tumor microenvironment was
shown in mice receiving B. breve or B. longum, compared to germ-free mice or mice natively without
Bifidobacterium in the GM. These findings were validated in a cohort of patients with metastatic melanoma,
where metagenomic sequencing revealed pre-treatment enrichment of B. longum, along with A.
muciniphila, Collinsella aerofaciens, and Enterococcus faecium, in those who responded to anti-PD-L1
[46]
immunotherapy . Furthermore, fecal microbiota transplantation into germ-free mice with responder GM
led to the restoration of anti-PD-L1 treatment efficacy. A study by Rong et al. suggested that
Bifidobacterium may potentiate the antitumor immune response by promoting the long-term survival of
CD8+ T cells as memory cells and thus stimulating the immune response in some immunotherapy
treatments . In another recent study, it was demonstrated that Bifidobacterium strains induce potent CD8+
[66]
T cell-mediated antitumor immunity in animal models, thus enhancing the treatment with immune
checkpoint inhibitors . Interestingly, several years earlier, Li et al. suggested a direct role of
[67]
Bifidobacterium spp. at the tumor site , by demonstrating their translocation from the gastrointestinal tract
[68]
into the bloodstream and selective accumulation in tumors, due to their ability to survive in the hypoxic,
nutrient-rich environment created by tumor cells . Furthermore, the potential of B. adolescentis as a highly
[69]
specific vector for the transport of anticancer genes to a target tumor has been demonstrated. In murine
models subcutaneously implanted with liver cancer cells, intravenous injection of B. adolescentis previously
transformed to express a gene encoding the antiangiogenic protein endostatin resulted in germination and
proliferation of microbes within the tumor bed, but not in non-malignant tissues. In addition, intratumoral
expression of endostatin and thus inhibition of tumor growth were observed.