T-Cell Phenotype Varies in Distinct Tumor Microenvironments and CD57 ⁺ T _FH Cells Are Associated with Disease Progression and Inferior Survival in Follicular Lymphoma

The tumor microenvironment plays a crucial role in mediating the tumor immune response, thereby affecting patient outcomes in follicular lymphoma (FL). Using CyTOF, we analyzed single cell suspensions created from pre-treatment biopsies in a cohort of 82 FL patients and retrospectively extracted patient clinical parameters. Hierarchical analysis of the tumor microenvironment composition stratified these patients into 4 groups: group 1 represents patients with high percentage of monocyte/macrophages/NK cells; patients from group 2 and 3 are rich of intratumoral T and B cells, respectively. Patients with intermediate number of T and B cells are classed into group 4. Intratumoral T cells from these 4 groups exhibited distinct phenotypical characteristics. Group 1 was enriched with KLRG1 ⁺CD8 ⁺ T cells, while group 4 showed increased number of CXCR3 ^- T _EM and CD4 ⁺ T _N cells. Patients from group 2 and 3 featured with increased number of ICOS ⁺ T _reg cells and CD57 ⁺ T _FH cells, respectively. We observed that higher numbers of T cells significantly correlated with early disease stage, lack of B-symptoms, event-free survival at 24 months (EFS24) and a favorable overall and EFS survival in patients with histological grade 1 and 2. However, this association was not seen in patients with histological grade 3a and b, suggesting that T cell-mediated anti-tumor immunity is preserved in low grade patients, but overridden in higher grade patients. CITRUS analysis revealed that a cluster that is CD57 ⁺ and PD-1 ^high was significantly more abundant in patients who had disease progression than patients who had a complete response to therapy, suggesting a role of CD57 ⁺ T _FH cells in promoting malignant cell growth in FL. Consistent with this finding, we observed that higher number of CD57 ⁺ T _FH cells correlated with an inferior survival in FL. Using CITE-seq technology, we found that CD57 ⁺ T _FH cells exhibited a substantially different transcriptome when compared to CD57 ^- T _FH cells. Genes that were differentially upregulated in CD57 ⁺ T _FH cells when compared to CD57 ^- T _FH cells included genes involved in cell survival, compromised inflammatory response, and metabolism activation including GZMK, CCL4, CST7, DUSP2, LGALS3, CYTOR, CHI3L2, SYNE2, CXCL13, CD27 and FABP5. Taken together, our results indicate different tumor microenvironments among FL patient groups that is associated with variable T-cell phenotype. We found that CD57 ⁺ T _FH cells play an important role in predicting disease progression and patient prognosis in FL.

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