Boosting γδ 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+ 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.

• Publication year

  2019

• Venue

  Oncoimmunology

• Publication date

  2019-03-04

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1080/2162402X.2018.1554175PMID 30723586PMCID PMC6350687
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• PD-1 blockade is proposed as a treatment strategy to boost γδ T cell anti-tumor functions in follicular lymphoma.

  Confidence 0.93

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• PD-1 expressed by most FL-infiltrating PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes with ADCC capacity impairs their cytolytic functions.

  Confidence 0.94

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• In MALC, PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes mediate direct cytolytic activity and anti-CD20 mAb-dependent antibody-dependent cellular cytotoxicity against follicular lymphoma cell aggregates.

  Confidence 0.95

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• A subset of follicular lymphoma cases shows a high immune escape phenotype with abundant infiltration by PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review

• antibody-dependent cellular cytotoxicity

  immune mechanism

  An Fc-mediated cytotoxic mechanism in which immune effector cells lyse antibody-coated target cells.

  Aliases: ADCC

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• anti-cd20 mabs

  therapeutic agent

  Monoclonal antibodies targeting CD20 that are used to engage Fc-dependent killing.

  Aliases: anti-CD20 monoclonal antibodies

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• follicular lymphoma

  condition

  A common non-Hodgkin lymphoma subtype examined here for immune escape and γδ T-cell activity.

  Aliases: FL

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• high immune escape phenotype

  phenotype

  An immune-evasion classification used for a subset of follicular lymphoma cases.

  Aliases: high immune-escape phenotype

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• malc

  assay

  A 3D co-culture assay used to test interactions between lymphoma cell aggregates and immune cells.

  Aliases: 3D co-culture assay

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• pd-1

  receptor

  An inhibitory immune checkpoint receptor expressed on lymphocytes.

  Aliases: PD1

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• pd-1 blockade

  therapy

  Intervention that blocks PD-1 signaling to relieve inhibitory immune signaling.

  Aliases: PD-1 inhibition

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• pd1+ cd16+ tcrvγ9vδ2 γδ t lymphocytes

  cell type

  A γδ T-cell subset defined by PD-1, CD16, and TCRVγ9Vδ2 expression.

  Aliases: PD1+ CD16+ TCRVγ9Vδ2 γδ T cells

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review
• γδ t cell anti-tumor functions

  cell function

  The tumor-killing effector activities attributed to γδ T cells in this lymphoma setting.

  Aliases: γδ T cell antitumor functions

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewB (s683577b42) review

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