Gut microbiome and anticancer immune response: really hot Sh*t!

Abstract

The impact of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer has been highlighted recently. Chemotherapeutic agents, by compromising, to some extent, the intestinal integrity, increase the gut permeability and selective translocation of Gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic Th17 T-cell responses are primed, facilitating the accumulation of Th1 helper T cells in tumor beds after chemotherapy as well as tumor regression. Importantly, the redox equilibrium of myeloid cells contained in the tumor microenvironment is also influenced by the intestinal microbiota. Hence, the anticancer efficacy of alkylating agents (such as cyclophosphamide) and platinum salts (oxaliplatin, cis-platin) is compromised in germ-free mice or animals treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host-microbe mutualism.

Figure 1

Mechanisms involved in the action of gut microbiota during cancer therapies. Certain chemotherapeutics (presumably those affecting the integrity of the gut barrier (1), e.g. CTX and oxaliplatin) facilitate the translocation of distinct bacteria or bacterial products (2) (Gram-positive for CTX), causing a cascade of systemic immune effects translating in the control of tumor outgrowth (3). Viaud et al. (2, 3) showed the role of specific Gram-positive commensal bacteria in the elicitation of pTh17 responses (2) associated with Th1 accumulation in tumor beds (3). Iida et al. demonstrated the role of ROS and TNF-producing myeloid cells conditioned by the presence of gut commensal bacteria in the efficacy of oxaliplatin and immunomodulators (4, 5), respectively, in triggering early tumor cytotoxicity. These effects account for the reduced efficacy of cytotoxic compounds in animals cotreated with broad-spectrum (or vancomycin or colistin) antibiotics (6)

Figure 2

Three ways to demonstrate that naive mice can get immunized against their commensal bacteria during CTX therapy. (Upper panel) Reconstitution (by oral gavage using L. johnsonii+E. hirae) of mice presterilized with broad-spectrum antibiotics (ATB) restores the pool of splenic pathogenic Th17 cells (coexpressing the transcription factors T-bet and RORγt). (Middle panel) Restimulation of splenic T cells from mice treated with CTX using syngeneic bone marrow-derived DCs loaded with distinct commensal bacteria (such as L. johnsonii or E. hirae) reactivates memory T cells that produce high levels of interferon-γ (IFNγ). (Lower panel) Adoptive transfer of TCR Tg CD4⁺ T cells recognizing a flagellin peptide of Clostridium into naive C57BL/6 mice treated or not with CTX. After 1 week, Tg T cells harboring a congenic marker can be analyzed by FACS to determine IL-17 production (in intracellular staining) as well as IFNγ release following restimulation of splenocytes with MHC class II-restricted flagellin peptides

Figure 3

Future prospects and clinical implementations of this work. To date, patients who are being diagnosed with cancer undergo a pathological biopsy and imaging tomography/magnetic resonance to analyze spreading of the malignant process. In the near future, we will need to investigate their intestinal microbiota and their systemic anticancer and antimicrobial immunity to be able to adapt/personalize the oncological therapy according to their microbial dysbiosis or immune dysfunctions. Specific food intake as well as probiotics composed of immunogenic (and safe) commensal/pathobionts could precede chemotherapeutics to facilitate their tumoricidal activity through bacterial adjuvantization