Both T cell priming in lymph node and CXCR3-dependent migration are the key events for predicting the response of atezolizumab

Sci Rep. 2021 Jul 6;11(1):13912. doi: 10.1038/s41598-021-93113-y.

Abstract

Anti-PD-L1 antibodies benefit many cancer patients, even those with "non-inflamed tumor". Determining which patients will benefit remains an important clinical goal. In a non-inflamed tumor mouse model, we found that PD-L1 was highly expressed on antigen-presenting cells (APCs) especially on CD103+ CD11c+ dendritic cells in tumor-draining lymph nodes (dLNs), suppressing T-cell priming by APCs. In this model, anti-PD-L1 antibodies enhanced T-cell priming and increased CXCR3+ activated T-cells in dLNs, which was followed by the trafficking of T-cells to tumors in response to CXCR3 ligands. As predictive biomarker, each APCs-related gene expression (AP score) alone or T-cells trafficking-related chemokine gene expression (T score) alone were still less than perfect among the 17 mouse models examined. However a combining score of AP score and T score (AP/T score) precisely identified anti-PD-L1-sensitive tumors. In the phase 3 trial of atezolizumab vs docetaxel in advanced NSCLC patients (OAK), the AP/T score could identify atezolizumab-treated NSCLC patients who achieved significant improvement in overall survival. This biomarker concept would be a clinically valuable for prediction of anti-PD-L1 antibody efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cross-Priming / drug effects
  • Cross-Priming / immunology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Ligands
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Models, Biological
  • Receptors, CXCR3 / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen
  • Ligands
  • Receptors, CXCR3
  • atezolizumab