Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome

Pitt, Jonathan M.; Vétizou, Marie; Waldschmitt, Nadine; Kroemer, Guido; Chamaillard, Mathias; Boneca, Ivo Gomperts; Zitvogel, Laurence

doi:10.1158/0008-5472.can-16-0448

Cited by 99 publications

(92 citation statements)

References 32 publications

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“…Inflammation also facilitates the expansion of microbes with oncogenic potential, including Fusobacterium nucleatum , enterotoxigenic B. fragilis or genotoxic E. coli 128–130 . The microbiota is also essential for the efficacy of antitumor immunity after chemotherapy or immunotherapy 14,131 . In mouse models, antitumor immunity induced by chemotherapy or blockade with antibodies to the checkpoint inhibitors CTLA-4 and PD-1 is abrogated after dysbiosis or in the absence of intestinal microbiota.…”

Section: Microbiota-driven Modulation Of the Host Immune Responsementioning

confidence: 99%

Regulation of inflammation by microbiota interactions with the host

et al. 2017

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The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.

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Section: Microbiota-driven Modulation Of the Host Immune Responsementioning

confidence: 99%

Regulation of inflammation by microbiota interactions with the host

et al. 2017

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“…Biomarkers of toxicity have been notoriously difficult to identify, however recent studies suggest that the immune microbiome plays a role in the development of toxicity (43–45). The microbiome may also be related to response to immune therapy, as seen in a recent report of a larger cohort of 228 patients with metastatic melanoma, nearly half of whom had been treated with anti-PD-1 therapy.…”

Section: An Understanding Of the Challenges And Limitations Unique Tomentioning

confidence: 99%

The Challenge for Development of Valuable Immuno-oncology Biomarkers

Mehnert

Monjazeb

Beerthuijzen

et al. 2017

Clinical Cancer Research

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The development of immunotherapy is an important breakthrough for the treatment of cancer, with anti-tumor efficacy observed in a wide variety of tumors. To optimize immunotherapy use, approaches must be developed to identify which patients are likely to achieve benefit. To minimize therapeutic toxicities and costs, understanding the ideal choice and sequencing of the numerous immuno-oncology agents available for individual patients is thus critical, but fraught with challenges. The immune tumor microenvironment (TME) is a unique aspect of the response to immuno-oncology agents and measurement of single biomarkers does not adequately capture these complex interactions. Therefore, multiple potential biomarkers are likely needed. Current candidates in this area include PD-L1 expression, CD8+ tumor infiltrating lymphocytes, tumor mutation load and neoantigen burden, immune related gene signatures and multiplex immunohistochemical assays that examine the pharmacodynamic and spatial interactions of the TME. The most fruitful investigations are likely to use several techniques to predict response and interrogate mechanisms of resistance. Immuno-oncology biomarker research must employ validated assays to ask focused research questions utilizing clinically annotated tissue collections and biomarker focused clinical trial designs to investigate specific endpoints. Real time input from patients and their advocates into biomarker discovery is necessary to ensure that the investigations pursued will improve both clinical outcomes and quality of life. We herein provide a framework of recommendations to guide the search for immuno-oncology biomarkers of value.

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“…The implications of this regulation are profound and bear significance well beyond the confines of the gastrointestinal tract. Importantly, a correlation between the composition of intestinal flora and degree of response to anti-tumor immunotherapy is established and beginning to be clinically exploited (36–38). The mechanisms accounting for the regulation and “fine-tuning” of immune responses in normal colonic epithelium are poorly understood (39).…”

Section: Discussionmentioning

confidence: 99%

Versican-Derived Matrikines Regulate Batf3–Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer

Hope

Emmerich

Papadas

et al. 2017

The Journal of Immunology

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Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. Here we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8+ T-cell infiltration in CRC, regardless of mismatch-repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T-cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8+ T-cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). The VCAN-derived matrikine, versikine, enhanced the generation of CD103+CD11chiMHCIIhi conventional dendritic cells (cDC) (homologous to Batf3-DC/CD8α+ DC/CD103+ DC/cDC1 subset/intratumoral DC2) from Flt3L-mobilized primary bone marrow-derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors towards IRF8- and BATF3-expressing cDC. Intratumoral BATF3-dependent DC are critical determinants for T-cell anti-tumor immunity, effector T cell trafficking to the tumor site and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents.

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Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome

Cited by 99 publications

References 32 publications

Regulation of inflammation by microbiota interactions with the host

Regulation of inflammation by microbiota interactions with the host

The Challenge for Development of Valuable Immuno-oncology Biomarkers

Versican-Derived Matrikines Regulate Batf3–Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer

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