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Colon
Original research
Autologous T cell responses to primary human colorectal cancer spheroids are enhanced by ectonucleotidase inhibition
  1. Julie Bonnereau1,
  2. Tristan Courau1,
  3. Nicolas Asesio2,
  4. Delphine Salfati2,
  5. Fatiha Bouhidel3,
  6. Hélène Corte4,
  7. Sarah Hamoudi1,
  8. Nassim Hammoudi1,2,
  9. Julie Lavolé1,
  10. Justine Vivier-Chicoteau1,2,
  11. Victor Chardiny1,
  12. Leon Maggiori4,
  13. Mathieu Blery5,
  14. Romain Remark5,
  15. Cécile Bonnafous6,
  16. Pierre Cattan4,
  17. Antoine Toubert1,
  18. Purnima Bhat7,8,
  19. Matthieu Allez1,2,
  20. Thomas Aparicio1,2,
  21. Lionel Le Bourhis1
  1. 1 INSERM U1160, Institut de Recherche Saint-Louis, Saint Louis Hospital, Université de Paris, Paris, France
  2. 2 Department of Hepato-Gastroenterology, Hôpital Saint-Louis, Paris, France
  3. 3 Anatomopathology Department, Hôpital Saint-Louis, Paris, France
  4. 4 Digestive Surgery Department, Hôpital Saint-Louis, Paris, France
  5. 5 Innate Pharma SA, Marseille, France
  6. 6 In Vivo Pharmacology, Innate Pharma SA, Marseille, France
  7. 7 Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
  8. 8 Gastroenterology and Hepatology Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia
  1. Correspondence to Dr Lionel Le Bourhis, INSERM U1160, Institut de Recherche Saint-Louis, Saint Louis Hospital, Université de Paris, Paris, France; lionel.le-bourhis{at}inserm.fr

Abstract

Objective T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type.

Design In a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response.

Results We show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures.

Conclusion In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.

  • COLORECTAL CANCER
  • CANCER IMMUNOBIOLOGY
  • IMMUNOTHERAPY
  • INTESTINAL T CELLS
  • EPITHELIAL CELLS

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/gutjnl-2021-326553

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Contributors Conceptualisation: LLB, JB, TC, AT and MA. Methodology: JB, TC, PB, RR and LLB. Investigation: JB, TC, NA, DS, JL, JV-C and RR. Resources: JB, VC, NA, DS, JV-C, JL, MB, CB, HC, LM and PC. Formal analysis: JB and TC. Writing—original draft: JB and LLB. Writing—review and editing: TC, TA, MA, PB and LLB. Funding acquisition: MA, LLB and TA. Supervision: MA, LLB and TA. Guarantor: MA, LLB and TA

    • Funding AT was supported by the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence ‘Milieu Intérieur’ Grant ANR-10- LABX-69-01. INSERM U1160 is a member of OPALE Carnot Institute. This work was financially supported by grants from Innate Pharma and La Ligue contre le Cancer, Ile de France.

    • Competing interests MA received grant supports from Innate Pharma, Janssen, Takeda and Genentech/Roche; and honorarium from teaching activities or consultancy from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Genentech, Gilead, IQVIA, Janssen, Novartis, Pfizer, Roche, Takeda, Tillots. TA presented conferences for Shire, Ipsen, Amgen, BMS, Servier, Pfizer, Roche Sanofi and meeting grants for Ipsen, Novartis, Roche and Hospira. He also obtained research grant from Novartis and Innate Pharma. MB, RR and CB were/are Innate Pharma employees.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.