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From mucosal infection to successful cancer immunotherapy

Nature Reviews Urology volume 20, pages 682–700 (2023)Cite this article

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Abstract

The clinical management of advanced malignancies of the upper and lower urinary tract has been revolutionized with the advent of immune checkpoint blockers (ICBs). ICBs reinstate or bolster pre-existing immune responses while creating new T cell specificities. Immunogenic cancers, which tend to benefit more from immunotherapy than cold tumours, harbour tumour-specific neoantigens, often associated with a high tumour mutational burden, as well as CD8+ T cell infiltrates and ectopic lymphoid structures. The identification of beneficial non-self tumour antigens and natural adjuvants is the focus of current investigation. Moreover, growing evidence suggests that urinary or intestinal commensals, BCG and uropathogenic Escherichia coli influence long-term responses in patients with kidney or bladder cancer treated with ICBs. Bacteria infecting urothelium could be a prominent target for T follicular helper cells and B cells, linking innate and cognate CD8+ memory responses. In the urinary tract, commensal flora differ between healthy and tumoural mucosae. Although antibiotics can affect the prognosis of urinary tract malignancies, bacteria can have a major influence on cancer immunosurveillance. Beyond their role as biomarkers, immune responses against uropathogenic commensals could be harnessed for the design of future immunoadjuvants that can be advantageously combined with ICBs.

Key points

  • The immune infiltrate of the urinary tract has prognostic and predictive value in kidney and bladder cancers.

  • Upper and lower urinary tract malignancies are not sterile.

  • Antibiotics compromise the efficacy of immune checkpoint inhibitors.

  • Cellular and humoral immune responses against uropathogenic Escherichia coli or BCG dictate the success of immune checkpoint inhibitors.

  • Novel therapeutic strategies should harness the urinary or intestinal microbiota.

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Fig. 1: The tumour microenvironment of muscle-invasive bladder cancer.
Fig. 2: Local microbiota and formation of tertiary lymphoid structures in response to immune checkpoint blockers.
Fig. 3: The tumour microenvironment of renal cell carcinoma.
Fig. 4: From mucosal infection or commensalism to effective immunomodulation during immune checkpoint blockade.

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Author notes

  1. These authors contributed equally: Anne-Gaëlle Goubet, Mathieu Rouanne.

Authors and Affiliations

  1. Gustave Roussy, Villejuif, France

    Anne-Gaëlle Goubet, Mathieu Rouanne, Lisa Derosa, Guido Kroemer & Laurence Zitvogel

  2. Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée — Ligue Nationale contre le Cancer, Villejuif, France

    Anne-Gaëlle Goubet, Mathieu Rouanne, Lisa Derosa & Laurence Zitvogel

  3. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland

    Anne-Gaëlle Goubet

  4. AGORA Cancer Center, Lausanne, Switzerland

    Anne-Gaëlle Goubet

  5. Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Mathieu Rouanne

  6. Faculté de Médecine, Université Paris-Saclay, Kremlin-Bicetre, France

    Lisa Derosa & Laurence Zitvogel

  7. Equipe labellisée par la Ligue contre le Cancer, Université de Paris Cité, Sorbonne Université, Institut Universitaire de France, Inserm U1138, Centre de Recherche des Cordeliers, Paris, France

    Guido Kroemer

  8. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  9. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France

    Guido Kroemer

  10. Center of Clinical Investigations for In Situ Biotherapies of Cancer (BIOTHERIS) INSERM, CIC1428, Villejuif, France

    Laurence Zitvogel

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Contributions

A.-G.G., M.R., L.D. and L.Z. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Laurence Zitvogel.

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Competing interests

L.Z. and A.-G.G. hold a patent entitled “A biomarker and compositions to increase the therapeutic index of neoadjuvant immunotherapy in muscle-invasive urothelial carcinoma” (No. PCT/EP2023/053977). L.Z. has held research contracts with 9 Meters Biopharma, Daiichi Sankyo and Pilege, and was on the Board of Directors of Transgene. L.Z. is a cofounder of everImmune, and its SAB President and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. Among these, patents were licensed to everImmune (US20210346438A1, US20200360449A1) and Transgene (US20200376052A1). L.D. is a consultant for everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. L.D. is a member of everImmune SAB. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys and Vascage. G.K. has been consulting for Reithera. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. Among these, patents were licensed to Bayer (WO2014020041-A1, WO2014020043-A1), Bristol Myers Squibb (WO2008057863-A1), Osasuna Therapeutics (WO2019057742A1), PharmaMar (WO2022049270A1 and WO2022048775-A1), Raptor Pharmaceuticals (EP2664326-A1), Samsara Therapeutics (GB202017553D0) and Therafast Bio (EP3684471A1). G.K.’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. M.R. declares no competing interests.

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Glossary

Culturomics

High-throughput culture approach optimizing bacterial culture techniques to uncover rare, under-represented, fastidious or hard-to-cultivate bacteria.

Tertiary lymphoid structures

(TLS). Ectopic lymphoid organs that develop in non-lymphoid tissues upon long-lasting exposure to inflammatory signals.

Urinary tract malignancies

Cancers affecting the urinary system (kidney, ureter, bladder and urethra) and the male reproductive system (penis, prostate and testicles). The latter is not dealt with in the present Review.

Urobiome

Microbiota contained in the normal ‘sterile’ urinary tract (without overt infection by pathogens).

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Goubet, AG., Rouanne, M., Derosa, L. et al. From mucosal infection to successful cancer immunotherapy. Nat Rev Urol 20, 682–700 (2023). https://doi.org/10.1038/s41585-023-00784-5

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