Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects

Abstract

The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound.

Immunomodulatory Activities of a Fungal Protein Extracted from Hericium erinaceus through Regulating the Gut Microbiota

“…Previous studies have shown that the efficacy of the anticancer immunomodulatory agent CTX relies on intestinal bacteria (43, 44), and high doses often damage the intestinal mucosa and metabolism, and probiotic bacteria such as Lactobacillus and Bifidobacterium can reduce intestinal mucosal injury and improve intestinal metabolism and intestinal microbiota (45, 46). In this study, CD3 + , CD4 + , CD8 + , CD28 + , and naive T cells were inhibited in high-dose cyclophosphamide-induced immunotoxicity mice after treatment with HEP3 (Figure 4), and also the immunohistochemistry of colon tissues in the IBD model rats showed the same results that Foxp3, IL-10, TNF-α, and NF-κB p65 improved to near normal (Figures 1C and 9), indicating that HEP3 might improve the immune function via regulating the proliferation and differentiation of T cells with the help of gut microbiota, but much more details need to be revealed.…”

A Blueprint to Advance Colorectal Cancer Immunotherapies

“…Numerous reports suggest that certain bacterial species have been disproportionally associated with colorectal cancer tumors and may contribute to disease pathogenesis (5,(59)(60)(61)(62)(63)(64). The microbiome plays a role in immunotherapy treatment outcomes in mouse models and humans (5,(65)(66)(67). In melanoma patients treated with ipilimumab, the presence of the Bacteroidetes phylum in feces correlated with resistance to the development of checkpoint blockade-induced colitis (68).…”

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

“…Other examples of essential prediction of treatment outcome come from the recognition of the impact of donor microbiota diversity and relative risk of premature death after hematopoietic stem cell transplantation [68], or between gut microbiome and prediction of chemotherapy-related bloodstream infection risk [69]. Finally, this stratification tool was elegantly exploited with the metagenome-profiling studies of patients that respond to the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed death 1 (PD-1) immune checkpoint inhibitors [70,71] and to cycloheximide [72]. This is being translated into the clinical practice in order to give efficient but toxic treatments only to patients that have a strong responder profile, and opens perspective of promoting responder profiles by adding live biotherapeutics (see below).…”