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

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⁺ TCRV?9V?2 ?? T lymphocytes. In a 3D co-culture assay (MALC), ?? 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 ?? T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated ?? T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting ?? T cell anti-tumor functions in FL.

SUBMITTER: Rossi C

PROVIDER: S-EPMC6350687 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

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

Rossi Cédric C Gravelle Pauline P Decaup Emilie E Bordenave Julie J Poupot Mary M Tosolini Marie M Franchini Don-Marc DM Laurent Camille C Morin Renaud R Lagarde Jean-Michel JM Ysebaert Loïc L Ligat Laetitia L Jean Christine C Savina Ariel A Klein Christian C Céspedes Alba Matas AM Perez-Galan Patricia P Fournié Jean-Jacques JJ Bezombes Christine C

Oncoimmunology 20181217 3

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 <i>in silico</i> analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant inf ...[more]

PMID: 30723586

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Project description:Although programmed cell death-1/programmed death-ligand 1 (PD-L1) inhibitors show remarkable antitumor activity, a large portion of patients with cancer, even those with high PD-L1-expressing tumors, do not respond to their effects. Most PD-L1 inhibitors contain modified fragment crystallizable region (Fc) receptor binding sites to prevent antibody-dependent cellular cytotoxicity (ADCC) against PD-L1-expressing non-tumor cells. However, natural killer (NK) cells have specific antitumor activity in the presence of tumor-targeting antibody through ADCC, which could enhance NK cell-induced cytotoxicity. We evaluated the antitumor efficacy of ADCC via anti-PD-L1 monoclonal antibodies (mAbs) and NK cells against several PD-L1-positive cancer cell lines. Various cancer cell lines were used as target cell lines. Surface PD-L1 expression was analyzed by flow cytometry. IMC-001 and anti-hPD-L1-hIgG1 were tested as anti-PD-L1 mAbs with ADCC and atezolizumab as an anti-PD-L1 mAb without ADCC. NK cell cytotoxicity was measured by 51Cr-release assay and CD107a degranulation assay. Also, live cell imaging was performed to evaluate cytotoxicity in a single-cell level. NK-92-CD16 (CD16-transduced NK-92 cell line) and peripheral blood mononuclear cells from healthy donors, respectively, were used as an effector cell. FcγRIIIa (CD16a)-V158F genotyping was performed for healthy donors. We demonstrated that the cytotoxicity of NK-92-CD16 cells toward PD-L1-positive cancer cell lines was significantly enhanced in the presence of anti-PD-L1 mAb with ADCC. We also noted a significant increase in primary human NK cell cytotoxicity against PD-L1-positive human cancer cells when cocultured with anti-PD-L1 mAb with ADCC. Moreover, NK cells expressing a FCGR3A high-affinity genotype displayed higher anti-PD-L1 mAb-mediated ADCC lysis of tumor cells than donors with a low-affinity genotype. These results suggest that NK cells induce an ADCC response in combination with anti-PD-L1 mAbs, which helps promote ADCC antitumor activity against PD-L1-positive tumors. This study provides support for NK cell immunotherapy against high PD-L1-expressing tumors in combination with ADCC through anti-PD-L1 mAbs.

Dataset Information

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

Publications

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

Similar Datasets

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