U1160 - Team 3 “Intestinal Immunity in Inflammation and Cancer” (M. Allez, A. Caignard)

Team leader: Matthieu ALLEZ PU-PH, AP-HP, HDR

 

 Deputy team leader: Anne CAIGNARD, DR2 Inserm, HDR

 

Composition

MOINS Helene (MCU-PH AP-HP, HDR)

LE BOURHIS Lionel (CRCN inserm)

APARICIO Thomas (PUPH AP-HP, HDR),

QUERO Laurent (PU-PH AP-HP)

GOERE Diane (PU-PH AP-HP, HDR)

BAUDRY Clotilde (PH AP-HP)

GORNET Jean-marc (PH AP-HP)

LOURENCO Nelson (PH AP-HP)

PEREZ Kevin (doctorant P7)

RETHACKER Louise (doctorante P7)

HAMMOUDI Nassim (doctorant P7)

BONNEREAU Julie (doctorante P7)

HAMOUDI Sarah (doctorante P7)

CHARDINY Victor (tech INSERM)

 

Main topic:

Our team is focused on the effector immune responses of lymphocytes, more specifically T cells and Innate Lymphoid Cells (ILC).

The group of Matthieu Allez studies the immune system in the intestinal mucosa. The intestine is a major exchange surface providing necessary nutrients to the organism and also a major portal of entry for pathogenic microbes. This dynamic tissue has to intensively renew in the face of microbial communities that induces an important stress on the epithelial layer. In the immune system reacts quickly to possible threats but is tolerant to antigens normally present in the lumen and monitors the renewal of the epithelium. Consequently, the specificities of the intestinal immune system play a particular role in this organ homeostasis and could be major factors in inflammatory bowel diseases (IBD) and in response to tumors such as colon cancers (CC).
The group of Anne Caignard studies the role of Innate Lymphoid Cells (ILC) including NK cells in the anti-tumor responses. Helper type ILC accumulate in tissues such as the intestinal mucosa, melanoma where they provide important homeostatic signals and participate to local immune responses. Their role in tumor immunosurveillance is not well defined. On the other hand NK cells are potent anti-tumor cytotoxic effectors that can be targeted by specific cancer immunotherapies. We address the regulation of ILC in the lymph node the first site of tumor dissemination in various cancers.
The group of Hélène Moins is focused on cutaneous T cell lymphomas and particularly its rare, aggressive and leukemic form represented by Sézary syndrome. Since the first description of an unprecedented immunological heterogeneity of tumoral cells (Sézary cells) by our team, our research is mainly focused on the characterization of Sézary cells both in blood and skin during disease evolution and treatments. We also address the critical questions about blood and skin immunological environments by studying the tumor and non-tumor cells, blood and skin responses to therapies, as well as the kinetics of immune reconstitution during and after therapy discontinuation

 

Scientific strategy:

Our studies focus on:

T cells and specific clonal expansions, and their impact in the physiopathology of Inflammatory Bowel Diseases
T cells on the effector anti-tumoral response to Colo-Rectal Cancers (CCR)
ILCs, including NK cells, in the response against solid tumors (breast, skin and CCR)
Sezary lymphomas, their differentiation and response to treatments.

We work exclusively on human samples provided by our close collaborations with clinical departments of Gastroenterology and Dermatology. We constitute large cohorts of patients recording clinical parameters and gathering associated tissues in a biobank. These samples allow two types of research:

i/ large scale "omic" approaches (exome, transcriptome, microbiome, proteome, metabolome)

ii/ ex-vivo assays on live primary cells (cytometry, functional response, organoids culture)

 

 

Our team is always looking for new members eager to study the human immune response with high clinical potential impact.

 

Main publication during the 2015-2020 period

 

1. Hammoudi N, Auzolle C, Tran Minh ML, Boschetti G, Bezault M, Buisson A, Pariente B, Treton X, Seksik P, Fumery M, Le Bourhis L, Nancey S, Allez M; REMIND study group. Postoperative Endoscopic Recurrence on the Neoterminal Ileum But Not on the Anastomosis Is Mainly Driving Long-Term Outcomes in Crohn's Disease. Am J Gastroenterol. 2020 May 22. doi: 10.14309/ajg.0000000000000638. Epub ahead of print. PMID: 32453052.

 

2. Bottois H, Ngollo M, Hammoudi N, Courau T, Bonnereau J, Chardiny V, Grand C, Gergaud B, Allez M, Le Bourhis L. KLRG1 and CD103 Expressions Define Distinct Intestinal Tissue-Resident Memory CD8 T Cell Subsets Modulated in Crohn's Disease. Front Immunol. 2020 May 12;11:896. doi: 10.3389/fimmu.2020.00896. PMID: 32477365; PMCID: PMC7235448.

 

3. Roelens M, de Masson A, Ram-Wolff C, Maki G, Cayuela JM, Marie-Cardine A, Bensussan A, Toubert A, Bagot M, Moins-Teisserenc H.; Revisiting the initial diagnosis and blood staging of mycosis fungoides and Sezary syndrome with the KIR3DL2 marker; Br J Dermatol. 2020;182(6):1415-1422.

 

4. Frazao A*, Rethacker L*, Jeudy G, Colombo M, Pasmant P, Avril MF, Toubert T, Moins-Teisserenc H, Roelens M, Dalac S, Maubec E, Caignard A. BRAF inhibitor resistance of melanoma cells triggers increased susceptibility to Natural Killer cell-mediated lysis. J Immunother Cancer, 2020;8:e000275. doi:10.1136/jitc-2019-000275

 

5. Hammoudi N, Cazals-Hatem D, Auzolle C, Gardair C, Ngollo M, Bottois H, Nancey S, Pariente B, Buisson A, Treton X, Fumery M, Bezault M, Seksik P, Le Bourhis L; REMIND Study Group Investigators, Flejou JF, Allez M. Association Between Microscopic Lesions at Ileal Resection Margin and Recurrence After Surgery in Patients With Crohn's Disease. Clin Gastroenterol Hepatol. 2020 Jan;18(1):141-149.e2. doi: 10.1016/j.cgh.2019.04.045. Epub 2019 Apr 28. PMID: 31042575.

 

6. Allez M, Auzolle C, Ngollo M, Bottois H, Chardiny V, Corraliza AM, Salas A, Perez K, Stefanescu C, Nancey S, Buisson A, Pariente B, Fumery M, Sokol H, Tréton X, Barnich N, Seksik P, Le Bourhis L; REMIND Study Group. T cell clonal expansions in ileal Crohn's disease are associated with smoking behaviour and postoperative recurrence. Gut. 2019 Nov;68(11):1961-1970. doi: 10.1136/gutjnl-2018-317878. Epub 2019 Feb 12. PMID: 30792246.

 

7. Frazao A, Rethacker L, Messaoudene M, Avril MF, Toubert A, Dulphy N, Caignard A. NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment. Front Immunol. 2019 Mar 29;10:661. doi: 10.3389/fimmu.2019.00661. PMID: 30984204; PMCID: PMC6449444.

 

8. Courau T, Bonnereau J, Chicoteau J, Bottois H, Remark R, Assante Miranda L, Toubert A, Blery M, Aparicio T, Allez M, Le Bourhis L. Cocultures of human colorectal tumor spheroids with immune cells reveal the therapeutic potential of MICA/B and NKG2A targeting for cancer treatment. J Immunother Cancer. 2019 Mar 14;7(1):74. doi: 10.1186/s40425-019-0553-9. PMID: 30871626; PMCID: PMC6417026.

 

9. Roelens M, Delord M, Ram-Wolff C, Marie-Cardine A, Alberdi A, Maki G, Homyrda L, Bensussan A, Bagot M, Toubert A, Moins-Teisserenc H.; Circulating and skin-derived Sezary cells: clonal but with phenotypic plasticity; Blood. 2017;130(12):1468-1471.

 

10. Messaoudene M, Frazao A, Gavlovsky PJ, Toubert A, Dulphy N, Caignard A. Patient's Natural Killer Cells in the Era of Targeted Therapies: Role for Tumor Killers. Front Immunol. 2017 Jun 12;8:683. doi: 10.3389/fimmu.2017.00683. PMID: 28659921; PMCID: PMC5466965.

 

11. Frazao A, Colombo M, Fourmentraux-Neves E, Messaoudene M, Rusakiewicz S, Zitvogel L, Vivier E, Vély F, Faure F, Dréno B, Benlalam H, Bouquet F, Savina A, Pasmant E, Toubert A, Avril MF, Caignard A. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600EMelanoma Lines with Vemurafenib. Cancer Immunol Res. 2017 Jul;5(7):582-593. doi: 10.1158/2326-6066.CIR-16-0380. Epub 2017 Jun 2. PMID: 28576831.

 

12. Allez M, Skolnick BE, Wisniewska-Jarosinska M, Petryka R, Overgaard RV. Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial. Gut. 2017 Nov;66(11):1918-1925. doi: 10.1136/gutjnl-2016-311824. Epub 2016 Aug 3. PMID: 27489241.

 

13. Messaoudene M, Fregni G, Enot D, Jacquelot N, Neves E, Germaud N, Garchon HJ, Boukouaci W, Tamouza R, Chanal J, Avril MF, Toubert A, Zitvogel L, Rusakiewicz S, Caignard A. NKp30 isoforms and NKp46 transcripts in metastatic melanoma patients: Unique NKp30 pattern in rare melanoma patients with favorable evolution. Oncoimmunology. 2016 Mar 10;5(12):e1154251. doi: 10.1080/2162402X.2016.1154251. PMID: 28123867; PMCID: PMC5214533.

 

14. Moins-Teisserenc H, Daubord M, Clave E, Douay C, Felix J, Marie-Cardine A, Ram-Wolff C, Maki G, Beldjord K, Homyrda L, Michel L, Bensussan A, Toubert A, Bagot M.; CD158k is a reliable marker for diagnosis of Sezary syndrome and reveals an unprecedented heterogeneity of circulating malignant cells; J Invest Dermatol. 2015;135(1):247-257.

 

15. Chirica M, Le Bourhis L, Lehmann-Che J, Chardiny V, Bouhidel F, Foulboeuf L, Gornet JM, Lourenco N, Dulphy N, Toubert A, Allez M. Phenotypic analysis of T cells infiltrating colon cancers: Correlations with oncogenetic status. Oncoimmunology. 2015 Apr 1;4(8):e1016698. doi: 10.1080/2162402X.2015.1016698. PMID: 26405567; PMCID: PMC4570110.

 

Major grants during the 2015-2020 period

Helmsley Charitable Trust for IBD research (2015)

Innate Pharma (2016)

Projet émergent Cancérople (2016)

ARC (2018)

SFD (2019, HM, AC)

Fond Amgen pour la Science et l’Humain (2020)

INCa PAIR Melanoma région Ile de France (2015)

Roche/Genentech: Braf inhibitors in cancer responses (2016)

Roche/Genentech: Etrolizumab in IBD treatment (2019)

La Ligue Région ile de France (2019)

ANR JCJC (2020)

 

Main networks

Groupe de Recherche sur les Maladies inflammatoires digestives (REMIND)

International collaboration within the IBD-OT network (Julian Panes, Barcelona and Dirk Haller, Munich)

Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID)

Société Française de Dermatologie (SFD)

Société Française d’Immunologie (SFI)

Groupe Français d’Etude sur les Lymphomes Cutanés (GFELC)

Immunotherapie translationnelle, Unité Immunité et Cancer, Curie Institute

Réseau CytHem

 

Alumni

Benjamin Pariente, PhD (2011-2013)

Mircea Chirica, PhD (2013-2015)

Tristan Courau, Post-Doctoral fellow (2016-2018)

Marjolaine Ngollo, Post-Doctoral fellow (2016-2019)

Hugo Bottois, PhD (2015-2019)

 

Myriam Messaoudene PhD (2012- 2015)

Alexandra Frazao, PhD (2014-2018)

Marina Colombo, Post-Doctoral fellow (2014-2015)

Pierre-Jean Gavlovsky, Post-Doctoral fellow (2016-2017)

 

Joana Felix, PhD (2012-2016)

Marie Roelens, PhD (2017-2020)