Tumor microenvironment of follicular lymphoma

Nath, Karthik; Tsang, Hennes; Gandhi, Maher K.

doi:10.21037/aol-20-55

Cited by 2 publications

(1 citation statement)

References 103 publications

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“…FL cells retain a remarkable dependency on the TME, orchestrating a tumor-permissive immune niche (reviewed in [12]). The FL TME is enriched with T follicular helper (T FH ) cells which express higher levels of IL-4 compared to T FH cells from healthy lymph nodes [13,14].…”

Section: Introductionmentioning

confidence: 99%

PARP14 is a novel target in STAT6 mutant follicular lymphoma

Mentz

Keay²,

Strobl³

et al. 2022

Leukemia

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The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

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Section: Introductionmentioning

confidence: 99%

PARP14 is a novel target in STAT6 mutant follicular lymphoma

Mentz

Keay²,

Strobl³

et al. 2022

Leukemia

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The follicular lymphoma tumor microenvironment at single-cell and spatial resolution

Radtke,

Roschewski

2024

Blood

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Follicular lymphoma (FL) is a generally incurable malignancy that originates from developmentally blocked germinal center (GC) B cells residing, primarily, within lymph nodes (LNs). During the long natural history of FL, malignant B cells often disseminate to multiple LNs and can affect virtually any organ. Non-malignant LNs are highly organized structures distributed throughout the body where they perform functions critical for host defense. In FL, the malignant B cells "re-educate" the lymphoid environment by altering the phenotype, distribution, and abundance of other cells such as T cells, macrophages, and subsets of stromal cells. Consequently, dramatic anatomical changes occur and include alterations in the number, shape, and size of neoplastic follicles with an accompanying attenuation of the T cell zone. Ongoing and dynamic interactions between FL B cells and the tumor microenvironment (TME) result in significant clinical heterogeneity observed both within and across patients. Over time, FL evolves into pathological variants associated with distinct outcomes, ranging from an indolent disease to more aggressive clinical courses with early death. Given the importance of both cell-intrinsic and extrinsic factors in shaping disease progression and patient survival, comprehensive examination of FL tumors is critical. Here, we describe the cellular composition and architecture of normal and malignant human LNs and provide a broad overview of emerging technologies for deconstructing the FL TME at single cell and spatial resolution. We additionally discuss the importance of capturing samples at landmark timepoints as well as longitudinally for clinical decision making.

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Tumor microenvironment of follicular lymphoma

Cited by 2 publications

References 103 publications

PARP14 is a novel target in STAT6 mutant follicular lymphoma

PARP14 is a novel target in STAT6 mutant follicular lymphoma

The follicular lymphoma tumor microenvironment at single-cell and spatial resolution

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