Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma

Cédric Rossi; Pauline Gravelle; Emilie Decaup; Julie Bordenave; Mary Poupot; Marie Tosolini; Don-Marc Franchini; Camille Laurent; Renaud Morin; Jean-Michel Lagarde; Loïc Ysebaert; Laetitia Ligat; Christine Jean; Ariel Savina; Christian Klein; Alba Matas Céspedes; Patricia Perez-Galan; Jean-Jacques Fournié; Christine Bezombes

doi:10.1080/2162402X.2018.1554175

Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma

Oncoimmunology. 2018 Dec 17;8(3):1554175. doi: 10.1080/2162402X.2018.1554175. eCollection 2019.

Authors

Cédric Rossi^{1

2

3

4

5}, Pauline Gravelle^{1

2

3

4

6}, Emilie Decaup¹, Julie Bordenave^{1

2

3

4}, Mary Poupot^{1

2

3

4}, Marie Tosolini^{1

2

3

7}, Don-Marc Franchini^{1

2

3

4}, Camille Laurent^{1

2

3

4

6}, Renaud Morin⁸, Jean-Michel Lagarde⁸, Loïc Ysebaert^{1

2

3

4

9}, Laetitia Ligat^{1

7}, Christine Jean¹, Ariel Savina¹⁰, Christian Klein¹¹, Alba Matas Céspedes¹², Patricia Perez-Galan¹², Jean-Jacques Fournié^{1

2

3

4}, Christine Bezombes^{1

2

3

4}

Affiliations

¹ Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR1037 INSERM, Université Toulouse III: Paul-Sabatier, ERL5294 CNRS, Université de Toulouse, Toulouse, France.
² Laboratoire d'Excellence TOUCAN, Toulouse, France.
³ Programme Hospitalo-Universitaire en Cancérologie CAPTOR, Toulouse, France.
⁴ CALYM Carnot Institute, Pierre-Bénite, France.
⁵ CHU Dijon, Hématologie clinique, Hôpital François Mitterand, Dijon, France.
⁶ Department of Pathology, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
⁷ Pôle Technologique du Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.
⁸ Imactiv 3D, Toulouse, France.
⁹ Department of Hematology, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
¹⁰ Institut Roche, Boulogne Billancourt, France.
¹¹ Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
¹² Hematology-Oncology department, IDIBAPS, Center Esther Koplowitz, Barcelona, Spain.

Abstract

Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1⁺ CD16⁺ TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL.

Keywords: 3D model; PD-1; anti-CD20 MAbs; follicular lymphoma; γδ T cells.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by institutional grants from INSERM, Université Paul Sabatier and CNRS, Laboratoire d’Excellence TOUCAN, Institut Hospitalo-Universitaire Programme CAPTOR and Roche.