Lack of intrafollicular memory CD4 + T cells is predictive of early clinical failure in newly diagnosed follicular lymphoma

Abstract

Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Cells in the microenvironment may be a key contributor to treatment failure. We used a discovery and validation study design to identify microenvironmental determinants of early failure and then integrated these results into the FLIPI. In total, 496 newly diagnosed FL grade 1–3 A patients who were prospectively enrolled into the MER cohort from 2002 to 2012 were evaluated. Tissue microarrays were stained for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRP-α, TIM3, PD-1, and PD-L1. Early failure was defined as failing to achieve event-free survival at 24 months (EFS24) in immunochemotherapy-treated patients and EFS12 in all others. CyTOF and CODEX analysis were performed to characterize intratumoral immunophenotypes. Lack of intrafollicular CD4 expression was the only predictor of early failure that replicated with a pooled OR 2.37 (95%CI 1.48–3.79). We next developed a bio-clinical risk model (BioFLIPI), where lack of CD4 intrafollicular expression moved patients up one FLIPI risk group, adding a new fourth high-risk group. Compared with BioFLIPI score of 1, patients with a score of 2 (OR 2.17; 95% CI 1.08–4.69), 3 (OR 3.53; 95% CI 1.78–7.54), and 4 (OR 8.92; 95% CI 4.00–21.1) had increasing risk of early failure. The favorable intrafollicular CD4 T cells were identified as activated central memory T cells, whose prognostic value was independent from genetic features. In conclusion, lack of intrafollicular CD4 expression predicts early failure in FL and combined with FLIPI improves identification of high-risk patients; however, independent validation is warranted.

Molecular Cytogenetic Profiling Reveals Similarities and Differences Between Localized Nodal and Systemic Follicular Lymphomas

“…Comparing GE data 20 of BCL2 -negative LFL with early progression and long-term survival showed an increased expression of genes involved in the recruitment of activated and cytotoxic T-cells in the long-term survivors, possibly providing a microenvironment more favorable to improved outcome (reviewed in 33 ). The impact of T-cells in FL pathogenesis was recently also shown by Mondello et al, 6 implementing the content of intrafollicular CD4-positive T-cells into the FLIPI and thereby generating a bio-clinical risk model (BioFLIPI). Of particular interest, an increased number of follicular T-helper cells has already been associated with early clinical FL stages, while those cells are less frequently observed in SFL.…”

Revealing the evolution of the tumor immune microenvironment in follicular lymphoma patients progressing within 24 months using single-cell imaging mass cytometry

“…Patients with follicular lymphoma (FL) who experience disease progression within 24 months (POD24) have inferior outcomes [ 1 , 2 ]. Current biological understanding of POD24 is mainly based on alterations acquired at the time of diagnosis of FL [ 3 ], including gene-mutation-based prognostic model POD24-PI [ 4 ] and TIME-based model BioFLIPI [ 5 ], but biological studies on POD24 stages are rare. TIME played an important role in the progression of FL [ 3 , 5 , 6 ].…”

“…Current biological understanding of POD24 is mainly based on alterations acquired at the time of diagnosis of FL [ 3 ], including gene-mutation-based prognostic model POD24-PI [ 4 ] and TIME-based model BioFLIPI [ 5 ], but biological studies on POD24 stages are rare. TIME played an important role in the progression of FL [ 3 , 5 , 6 ]. However, due to the lack of technologies that enable comprehensive spatial analysis at single-cell resolution with high-throughput phenotypic information, the evolution of TIME over the course of POD24 remains elusive.…”

Immune Epigenetic Crosstalk Between Malignant B Cells and the Tumor Microenvironment in B Cell Lymphoma

“…Despite retaining the characteristics of the primary site of development, the cellular composition and spatial arrangement of the TME mirror the genetic complexity and tumor type ( Scott and Gascoyne, 2014 ). Accordingly, the TME has shown a close association with treatment failure and outcome ( Dave et al, 2004 ; Kotlov et al, 2021 ; Mondello et al, 2021 ). Here we provide an overview of the most frequent epigenetic mechanisms associated with B cell lymphoma ( Figure 1 , 2 and Table 1 ) and discuss the therapeutic options to revert their oncogenic and immunosuppressive effect.…”