Modulation of blood T cell polyfunctionality and HVEM/BTLA expression are critical determinants of clinical outcome in anti-PD1-treated metastatic melanoma patients

Oncoimmunology. 2024 Jun 26;13(1):2372118. doi: 10.1080/2162402X.2024.2372118. eCollection 2024.

Abstract

The need for reliable biomarkers to predict clinical benefit from anti-PD1 treatment in metastatic melanoma (MM) patients remains unmet. Several parameters have been considered in the tumor environment or the blood, but none has yet achieved sufficient accuracy for routine clinical practice. Whole blood samples from MM patients receiving second-line anti-PD1 treatment (NCT02626065), collected longitudinally, were analyzed by flow cytometry to assess the immune cell subsets absolute numbers, the expression of immune checkpoints or ligands on T cells and the functionality of innate immune cells and T cells. Clinical response was assessed according to Progression-Free Survival (PFS) status at one-year following initiation of anti-PD1 (responders: PFS > 1 year; non-responders: PFS ≤ 1 year). At baseline, several phenotypic and functional alterations in blood immune cells were observed in MM patients compared to healthy donors, but only the proportion of polyfunctional memory CD4+ T cells was associated with response to anti-PD1. Under treatment, a decreased frequency of HVEM on CD4+ and CD8+ T cells after 3 months of treatment identified responding patients, whereas its receptor BTLA was not modulated. Both reduced proportion of CD69-expressing CD4+ and CD8+ T cells and increased number of polyfunctional blood memory T cells after 3 months of treatment were associated with response to anti-PD1. Of upmost importance, the combination of changes of all these markers accurately discriminated between responding and non-responding patients. These results suggest that drugs targeting HVEM/BTLA pathway may be of interest to improve anti-PD1 efficacy.

Keywords: Advanced melanoma; HVEM; T cell polyfunctionality; anti-PD1; biomarkers of response; blood immuno-monitoring.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Male
  • Melanoma* / drug therapy
  • Melanoma* / immunology
  • Melanoma* / pathology
  • Middle Aged
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / metabolism
  • Receptors, Immunologic* / metabolism
  • Receptors, Tumor Necrosis Factor, Member 14* / metabolism
  • Treatment Outcome

Substances

  • BTLA protein, human
  • Immune Checkpoint Inhibitors
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNFRSF14 protein, human

Grants and funding

This work was financially supported by grants from the PAIR Melanome program (INCa-2017-022 and DGOS 2017-022), the MELPREDICT program (INCa-DGOS PRT-K2016-051), the SIRIC project (LYriCAN+, INCa-DGOS-INSERM-ITMO cancer_18003), the Bristol-Meyers Squibb foundation for research in immuno-oncology (BMS-1604-01-015), the Région Rhône Alpes (IRICE Project: RRA18-010792-01–10365). This work was performed within the framework of the LABEX DEVweCAN (ANR-10-LABX-0061) of the University of Lyon, within the program “Investissements d’Avenir” (ANR-11-IDEX-0007) organized by the French National Research Agency. We also thank the Institut Convergence Plascan (Grant Number ANR-17-CONV-0002) for their support.