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Role of the microbiota in response to and recovery from cancer therapy

Nature Reviews Immunology volume 24, pages 308–325 (2024)Cite this article

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Abstract

Our understanding of how the microbiota affects the balance between response to and failure of cancer treatment by modulating the tumour microenvironment and systemic immune system has advanced rapidly in recent years. Microbiota-targeting interventions in patients with cancer are an area of intensive investigation. Promisingly, phase I–II clinical trials have shown that interventions such as faecal microbiota transplantation can overcome resistance to immune checkpoint blockade in patients with melanoma, improve therapeutic outcomes in treatment-naive patients and reduce therapy-induced immunotoxicities. Here, we synthesize the evidence showing that the microbiota is an important determinant of both cancer treatment efficacy and treatment-induced acute and long-term toxicity, and we discuss the complex and inter-related mechanisms involved. We also assess the potential of microbiota-targeting interventions, including bacterial engineering and phage therapy, to optimize the response to and recovery from cancer therapy.

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Fig. 1: The host and tumour microbiota shape the tumour microenvironment.
Fig. 2: The gut microbiota modulates the immunotoxicities induced by conventional and emerging cancer therapies.
Fig. 3: Mechanisms by which the microbiota modulates the efficacy of cancer (immuno)therapies.
Fig. 4: Emerging microbiota-targeting strategies.

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Acknowledgements

This work was supported by Ideas grants 1180799 and 2018793 awarded to D.J.L. and S.J.B. from the Australian National Health and Medical Research Council, the Australian Medical Research Future Fund (MRF2007441), the Leukaemia Foundation of Australia and a Tour De Cure Pioneering Research Grant (RSP-264–18/19). Y.W. is supported by a Melanoma Research Alliance grant (no.937368), the Rosetrees Trust (no. MYIA\100002), a research grant from Pfizer and the Lemelbaum family.

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Author notes

  1. These authors contributed equally: Stephen J. Blake, Yochai Wolf.

  2. These authors jointly supervised this work: Ben Boursi, David J. Lynn.

Authors and Affiliations

  1. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    Stephen J. Blake & David J. Lynn

  2. College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia

    Stephen J. Blake & David J. Lynn

  3. Ella Lemelbaum Institute for Immuno-oncology and Skin Cancer, Sheba Medical Center, Tel Hashomer, Israel

    Yochai Wolf

  4. Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Yochai Wolf

  5. School of Medicine, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ben Boursi

  6. Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel

    Ben Boursi

  7. Center of Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA

    Ben Boursi

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All authors researched data for the article, contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to David J. Lynn.

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Competing interests

S.J.B. and D.J.L. are co-inventors on International Patent Application No. PCT/AU2020/051278 related to this area of research. D.J.L. has received funding from GSK for research not related to this Review. Y.W. receives a research grant from Pfizer for research not related to this Review. B.B. declares no competing interests.

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Glossary

Chimeric antigen receptor T cells

(CAR T cells). A form of cell-based immunotherapy generated from donor T cells that are transduced with a construct that, at a minimum, expresses a B cell receptor against a leukaemic target such as CD19, CD20 or BCMA, coupled with a co-stimulatory receptor such as CD137 or CD28.

Cytokine release syndrome

(CRS). A form of systemic inflammatory response syndrome characterized by increased serum cytokine levels that can be triggered by various factors including infection and immunotherapies.

Dysbiosis

Disruption of the normal, homeostatic composition and function of a microbiota within its ecological niche.

Faecal microbiota transplantation

(FMT). The transfer of faecal material from a donor to a recipient by lower or upper gastrointestinal tract endoscopy, enema or consumption of capsules of freeze-dried material. FMT describes both a clinical intervention and a tool for research purposes, such as xenotransplantation (FMT from human to mouse).

Graft-versus-host disease

(GVHD). A life-threatening condition that arises following haematopoietic cell transplantation (HCT) whereby donor immune cells in the graft attack host cells, often in the skin, liver and gastrointestinal tract.

Haematopoietic cell transplantation

(HCT). The transplantation of multipotent haematopoietic stem cells, usually derived from the bone marrow, peripheral blood or umbilical cord blood, which replicate and differentiate inside the recipient to produce additional normal blood cells.

Immune-agonist antibodies

(IAAs). Antibodies against co-activating or co-stimulatory receptors, such as members of the tumour necrosis factor receptor superfamily that includes CD40 and CD137, that induce immune-activating responses upon receptor binding.

Immune checkpoint blockade

(ICB). Inhibition of the interactions between immune checkpoint molecules and their ligands, such as between PD1 and PDL1 or between CTLA4 and CD80 or CD86, which blocks checkpoint-induced immune exhaustion.

Immune effector cell-associated neurotoxicity syndrome

(ICANS). A clinical and neuropsychiatric syndrome that can occur in the days to weeks following administration of certain types of immunotherapy, particularly immune effector cell therapies such as chimeric antigen receptor T cells (CAR T cells) and T cell-engaging therapies.

Immune-related adverse events

(irAEs). Autoimmune or inflammatory-like conditions that arise during immunotherapy, such as colitis, dermatitis and hepatitis.

Postbiotics

A preparation of inanimate microorganisms and/or their components that confers a health benefit to the host.

Prebiotics

Substrates that are selectively used by host microorganisms conferring a health benefit.

Probiotics

Live microorganisms that, when administered in adequate amounts, confer a health benefit to the host.

Short-chain fatty acids

(SCFAs). A group of immunomodulatory metabolites produced by various families of anaerobic bacteria, such as Clostridium, Bifidobacterium and Lactobacillus spp., through anaerobic fermentation of dietary fibre in the colon.

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Blake, S.J., Wolf, Y., Boursi, B. et al. Role of the microbiota in response to and recovery from cancer therapy. Nat Rev Immunol 24, 308–325 (2024). https://doi.org/10.1038/s41577-023-00951-0

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