Low frequency of Vγ9Vδ2 T cells predicts poor survival in newly diagnosed acute myeloid leukemia.

ABSTRACT: In several tumor subtypes, an increased infiltration of Vγ9Vδ2 T cells has been shown to have the highest prognostic value compared with other immune subsets. In acute myeloid leukemia (AML), similar findings have been based solely on the inference of transcriptomic data and have not been assessed with respect to confounding factors. This study aimed at determining, by immunophenotypic analysis (flow or mass cytometry) of peripheral blood from patients with AML at diagnosis, the prognostic impact of Vγ9Vδ2 T-cell frequency. This was adjusted for potential confounders (age at diagnosis, disease status, European LeukemiaNet classification, leukocytosis, and allogeneic hematopoietic stem cell transplantation as a time-dependent covariate). The cohort was composed of 198 patients with newly diagnosed (ND) AML. By univariate analysis, patients with lower Vγ9Vδ2 T cells at diagnosis had significantly lower 5-year overall and relapse-free survivals. These results were confirmed in multivariate analysis (hazard ratio [HR], 1.55 [95% confidence interval (CI), 1.04-2.30]; P = .030 and HR, 1.64 [95% CI, 1.06-2.53]; P = .025). Immunophenotypic alterations observed in patients with lower Vγ9Vδ2 T cells included a loss of some cytotoxic Vγ9Vδ2 T-cell subsets and a decreased expression of butyrophilin 3A on the surface of blasts. Samples expanded regardless of their Vγ9Vδ2 T-cell levels and displayed similar effector functions in vitro. This study confirms the prognostic value of elevated Vγ9Vδ2 T cells among lymphocytes in patients with ND AML. These results provide a strong rationale to consider consolidation protocols aiming at enhancing Vγ9Vδ2 T-cell responses.

Targeting BTN2A1 enhances Vγ9Vδ2 T-cell effector functions and triggers tumor cell pyroptosis.

Vγ9Vδ2 T cells are potent but elusive cytotoxic effectors. Butyrophilin subfamily 2 member A1 (BTN2A1) is a surface protein that has recently been shown to bind the Vγ9 chain of the γδ T-cell receptor (TCR) but its precise role in modulating Vγ9Vδ2 T-cell functions remains unknown. Here, we show that 107G3B5, a monoclonal BTN2A1 agonist antibody, was able to significantly enhance Vγ9Vδ2 T-cell functions against hematological or solid cell lines and against primary cells from adult acute lymphoblastic leukemia patients. New computer vision strategies applied to holotomographic microscopy videos showed that 107G3B5 enhanced the interaction between Vγ9Vδ2 T cells and target cells in a quantitative and qualitative manner. In addition, we found that Vγ9Vδ2 T cells activated by 107G3B5 induced caspase 3/7 activation in tumor cells, thereby triggering tumor cell death by pyroptosis. Together, these data demonstrate that targeting BTN2A1 with 107G3B5 enhances the Vγ9Vδ2 T-cell antitumor response by triggering the pyroptosis-induced immunogenic cell death. These new pyroptosis-based therapies have great potential to stimulate the immune system to fight cancer, especially "cold" tumors.

Prognostic Immune Effector Signature in Adult Acute Lymphoblastic Leukemia Patients Is Dominated by γδ T Cells.

The success of immunotherapy has highlighted the critical role of the immune microenvironment in acute lymphoblastic leukemia (ALL); however, the immune landscape in ALL remains incompletely understood and most studies have focused on conventional T cells or NK cells. This study investigated the prognostic impact of circulating γδ T-cell alterations using high-dimensional analysis in a cohort of newly diagnosed adult ALL patients (10 B-ALL; 9 Philadelphia+ ALL; 9 T-ALL). Our analysis revealed common alterations in CD8+ T cells and γδ T cells of relapsed patients, including accumulation of early stage differentiation and increased expression of BTLA and CD73. We demonstrated that the circulating γδ T-cell signature was the most discriminating between relapsed and disease-free groups. In addition, Vδ2 T-cell alterations strongly discriminated patients by relapse status. Taken together, these data highlight the role of ɣδ T cells in adult ALL patients, among whom Vδ2 T cells may be a pivotal contributor to T-cell immunity in ALL. Our findings provide a strong rationale for further monitoring and potentiating Vδ2 T cells in ALL, including in the autologous setting.

BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells.

The anti-tumor response of Vγ9Vδ2 T cells requires the sensing of accumulated phosphoantigens (pAgs) bound intracellularly to butyrophilin 3A1 (BTN3A1). In this study, we show that butyrophilin 2A1 (BTN2A1) is required for BTN3A-mediated Vγ9Vδ2 T cell cytotoxicity against cancer cells, and that expression of the BTN2A1/BTN3A1 complex is sufficient to trigger Vγ9Vδ2 TCR activation. Also, BTN2A1 interacts with all isoforms of BTN3A (BTN3A1, BTN3A2, BTN3A3), which appears to be a rate-limiting factor to BTN2A1 export to the plasma membrane. BTN2A1/BTN3A1 interaction is enhanced by pAgs and, strikingly, B30.2 domains of both proteins are required for pAg responsiveness. BTN2A1 expression in cancer cells correlates with bisphosphonate-induced Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell killing of cancer cells is modulated by anti-BTN2A1 monoclonal antibodies (mAbs), whose action relies on the inhibition of BTN2A1 binding to the Vγ9Vδ2TCR. This demonstrates the potential of BTN2A1 as a therapeutic target and adds to the emerging butyrophilin-family cooperation pathway in γδ T cell activation.

Socioeconomic deprivation is associated with decreased survival in patients with acute myeloid leukemia.

BACKGROUND: Socioeconomic deprivation is associated with poor prognosis in patients with solid tumors. However, few studies have assessed the association between socioeconomic parameters and prognosis in Acute Myeloid Leukemia (AML), and these report conflicting results. Our monocentric study assessed the impact of socioeconomic deprivation using the validated EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score in a prospective cohort of intensively treated AML patients. METHODS: EPICES questionnaires were given to patients receiving intensive chemotherapy for newly diagnosed AML at the Paoli Calmettes Institute between July 2012 and December 2014. Study participants were categorized as non-deprived (score <30.17), deprived (score 30.17-48.51), or very-deprived (score ≥ 48.52). The primary endpoint was Overall Survival (OS). The independence of EPICES score effects was analyzed via Cox regression with adjustment for confounding factors. RESULTS: 209 AML patients received the questionnaire, 149 (71.3 %) patients responded. The median EPICES score was 23.6; 26.8 % and 10.1 % of patients were deprived and very deprived, respectively. OS was 23.16 months (95 %CI [17.15-33.31]). According to multivariate analysis, a very-deprived EPICES score, European Leukemia Net categories, age, smoking, and the absence of allogeneic stem cell transplantation were independent factors associated with decreased OS. CONCLUSION: Our results underscore the importance of integrating nonbiological factors in the prognostic stratification of AML patients. The very deprived population exhibited worse OS, confirming that socioeconomic parameters play a role in patient outcomes in AML. Very deprived patients with AML should receive specific attention and adapted clinical management.