Romain Daillère

Institut Gustave Roussy

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Laurence Zitvogel

Institut Gustave Roussy

Guido Kroemer

Université Paris Cité

Lisa Derosa

Inserm

Bertrand Routy

Centre Hospitalier de l’Université de Montréal

Safae Terrisse

Hôpital Saint-Louis

Ivo G. Boneca

Institut Pasteur

Anne‐Gaëlle Goubet

Université Paris-Saclay

Antoine Desîlets

Centre Hospitalier de l’Université de Montréal

Carolina Alves Costa Silva

Institut Gustave Roussy

Caroline Flament

Institut Gustave Roussy

Cooperative Institutions

Inserm

215

Institut Gustave Roussy

142

Université Paris-Saclay

119

Centre National de la Recherche Scientifique

Université Paris Cité

La Ligue Contre le Cancer

Istituti di Ricovero e Cura a Carattere Scientifico

Université Paris-Sud

Memorial Sloan Kettering Cancer Center

Assistance Publique – Hôpitaux de Paris

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Table S1 from Microbiota-Centered Interventions: The Next Breakthrough in Immuno-Oncology?

Lisa Derosa Bertrand Routy Antoine Desîlets Romain Daillère Safae Terrisse

<p>Supplementary Table S1</p>

Table (database)

10.1158/2159-8290.22540048.v1

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Bacteria-specific CXCL13-producing follicular helper T cells are putative prognostic markers to neoadjuvant PD-1 blockade in muscle-invasive urothelial carcinoma.

Journal of Clinical Oncology (2022)

Anne‐Gaëlle Goubet Carolina Alves Costa Silva Leonardo Lordello de Melo Marianne Gazzano C. Lebâcle

535 Background: Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, have emerged as a successful immunotherapeutic strategy for advanced and metastatic urothelial cancer (UC). Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies leads to durable tumor regressions in up to 25% metastatic muscle invasive UC (MIBC). Neoadjuvant use of ICI also showed remarkable efficacy and represents a unique opportunity to study immunodynamics during PD-1 blockade to decipher functional predictors of response and resistance. Methods: Patients diagnosed with T2-T4aN0M0 MIBC were treated with 3 cycles of neoadjuvant pembrolizumab before cystectomy in the PANDORE trial (NCT03212651). The primary endpoint was pathologic complete response (ypT0N0). Secondary endpoints focused on safety, progression-free survival (PFS) and biomarker analysis. We performed longitudinal analysis of peripheral and tumor infiltrating lymphocytes, tumor microbiome as well as soluble factors using high dimensionnal immune phenotyping by mass cytometry, immuno-fluorescence and -histochemistry and multiplex immunoassays. Humoral and cellular recall immune memory against urinary tract commensals were studied. Results: Thirty-nine patients were enrolled from October 2017 to December 2019. All but 5 (n = 34 patients (87.2%)) proceeded with cystectomy. Ten patients presented with ypT0N0 (29.4%; 95% CI: 15.1 %-47.5 %). Multidimensional biomarkers analysis showed that baseline follicular T helper (Tfh) and post-pembrolizumab tertiary lymphoid structure (TLS) and activated B cells were associated with outcome ( p= 0.005, p= 0.01 and p= 0.04, respectively). Plasma CXCL13 (the prototypic chemokine secreted by Tfh and involved in TLS functions) increased after 1 cycle of PD-1 blockade in responders and patients without progression at 24 months ( p= 0.002 and p= 0.0001, respectively). Focusing on MIBC tumor microbiome, we showed that intracellular Gram negative bacteria and other commensals were more frequent in tumoral than in normal urothelium ( p= 0.04). Interestingly, basal CXCL13-secreting CD4 + T cells and IgG directed against urinary pathobionts such as Escherichia coli predicted prolonged PFS ( p= 0.01 and p= 0.001, respectively). Conclusions: Our results suggest that urothelial commensals could induce specific Tfh and B cell responses that were re-invigorated by PD-1 blockade and associated with clinical benefit to pembrolizumab. Further analyses are needed to validate the predictive value of commensal-specific Tfh in UC and other epithelial cancers that are directly or indirectly exposed to bacteria. Clinical trial information: NCT03212651.

Immune checkpoint

CXCL13

10.1200/jco.2022.40.6_suppl.535

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Citations (5)

Table S3 from Microbiota-Centered Interventions: The Next Breakthrough in Immuno-Oncology?

Lisa Derosa Bertrand Routy Antoine Desîlets Romain Daillère Safae Terrisse

<p>Supplementary Table S3</p>

Table (database)

10.1158/2159-8290.22540042.v1

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Oral administration of Akkermansia muciniphila elevates systemic antiaging and anticancer metabolites

Aging (2021)

Claudia Grajeda‐Iglesias Sylvère Durand Romain Daillère Kristina Iribarren Fabien Lemaître

teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Akkermansia muciniphila

10.18632/aging.202739

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The Impact of the Intestinal Microbiota in Therapeutic Responses Against Cancer

OncoImmunology (2017)

Mélodie Bonvalet Romain Daillère María P. Roberti Conrad Rauber Laurence Zitvogel

In the last years, there is a growing awareness regarding the role of the microbiota in various chronic inflammatory disorders including cancers. The intestinal microbiome is not only regulating the spontaneous course of malignancies of the digestive tract but also acts at a distant site on extraintestinal neoplasia, to play a beneficial or a detrimental role, depending on the context. By providing pathogen and damage-associated molecular patterns and by activating local and distant antigen-presenting cells, our commensals modulate not only the gut, the systemic inflammatory, and immune tonus but also the tumor microenvironment and anticancer-specific adaptive immune responses. Additionally, therapeutic interventions alter the delicate balance between the epithelium, the microbial community, and the lamina propria immunity, influencing the clinical outcome. This chapter will focus on the impact of the intestinal composition in the bioactivity and therapeutic efficacy of distinct compounds (alkylating agents, platinum salts, radiotherapy, conditioning regimen for stem cell transplantation, immunotherapies, and immune checkpoint blockers). This era of research opens novel therapeutic avenues that aim to restore gut eubiosis for a better clinical outcome in cancer patients.

Lamina propria

10.1007/978-3-319-62431-0_27

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Rôle du microbiote intestinal dans la réponse aux thérapies anti-tumorales

Biologie Aujourd hui (2017)

Marie Vétizou Romain Daillère Laurence Zitvogel

The gut microbiota is known to affect digestion, protection against pathogens infection, immune system maturation and enteric nervous system development, but others links have also been established with diabetes, obesity, autism and cancer. Lately, bacterial species from the gut have been involved in tumor immunosurveillance. Natural or mediated by treatment such as chemotherapy or immunotherapy, anti-tumoral immune responses seem to rely on gut microbiota. The bacteria involved and their mechanisms of action are different according to the treatment of interest. Nevertheless, modulation of gut microbiota represents a great potential with the development of onco-micro-biotics to optimize the response to cancer therapies.

Immunosurveillance

10.1051/jbio/2017009

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Harnessing the Intestinal Microbiome for Optimal Therapeutic Immunomodulation

Cancer Research (2014)

Sophie Viaud Romain Daillère Ivo G. Boneca Patricia Lepage Mikaël J. Pittet

Abstract Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens. Cancer Res; 74(16); 4217–21. ©2014 AACR.

10.1158/0008-5472.can-14-0987

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The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide

Science (2013)

Sophie Viaud Fabiana Saccheri Grégoire Mignot Takahiro Yamazaki Romain Daillère

The Microbiota Makes for Good Therapy The gut microbiota has been implicated in the development of some cancers, such as colorectal cancer, but—given the important role our intestinal habitants play in metabolism—they may also modulate the efficacy of certain cancer therapeutics. Iida et al. (p. 967 ) evaluated the impact of the microbiota on the efficacy of an immunotherapy [CpG (the cytosine, guanosine, phosphodiester link) oligonucleotides] and oxaliplatin, a platinum compound used as a chemotherapeutic. Both therapies were reduced in efficacy in tumor-bearing mice that lacked microbiota, with the microbiota important for activating the innate immune response against the tumors. Viaud et al. (p. 971 ) found a similar effect of the microbiota on tumor-bearing mice treated with cyclophosphamide, but in this case it appeared that the microbiota promoted an adaptive immune response against the tumors.

10.1126/science.1240537

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Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer

Nature Medicine (2022)

Lisa Derosa Bertrand Routy Andrew Maltez Thomas Valerio Iebba Gérard Zalcman

Akkermansia muciniphila

Akkermansia

10.1038/s41591-021-01655-5

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Citations (370)

Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma

Journal of Clinical Investigation (2016)

Nicolas Jacquelot David Enot Caroline Flament Nadège Vimond C Blattner

Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.

CXCR5

CXCR3

Homing (biology)

CCR10

10.1172/jci80071

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Citations (67)