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

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

Stéphane Dalle  1   2 , Estelle Verronese  3 , Axelle N'Kodia  3 , Christine Bardin  3 , Céline Rodriguez  2   3 , Thibault Andrieu  2   3 , Anais Eberhardt  1   2 , Gabriel Chemin  2 , Uzma Hasan  3 , Myrtille Le-Bouar  1 , Julie Caramel  2 , Mona Amini-Adle  1 , Nathalie Bendriss-Vermare  2   3 , Bertrand Dubois  2   3 , Christophe Caux  2   3 , Christine Ménétrier-Caux  2   3
Affiliations
Clinical Trial

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

Stéphane Dalle et al. Oncoimmunology. .

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.

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Conflict of interest statement

SD received institutional research grants from MSD, BMS and Pierre Fabre companies.

Figures

Figure 1.
Figure 1.
Melanoma patients present several alterations in peripheral immune cells compared to HD.
Figure 2.
Figure 2.
Melanoma patients present increased expression of different ICP on T cells subsets.
Figure 3.
Figure 3.
Melanoma patients blood immune cells present reduced capacity to produce cytokines compared to HD.
Figure 4.
Figure 4.
Decreased HVEM expression on T cells in patients responding to treatment.
Figure 5.
Figure 5.
Decreased HVEM expression on T cells after 3 months of treatment in responding patients.
Figure 6.
Figure 6.
Increased memory T cell absolute number and polyfunctionality under treatment in responding patients.
Figure 7.
Figure 7.
The biomarkers of interest selected in this study allow to discriminate responding from non-responding patients.
See this image and copyright information in PMC

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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.