IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment

Leca, Julie; Lemonnier, Franҫois; Meydan, Cem; Foox, Jonathan; Ghamrasni, Samah El; Mboumba, Diana-Laure; Duncan, Gordon S.; Fortin, Jérôme; Sakamoto, Takashi; Tobin, Chantal; Hodgson, Kate; Haight, Jillian; Smith, Logan K.; Elia, Andrew; Butler, Daniel; Berger, Thorsten; Leval, Laurence de; Mason, Christopher E.; Melnick, Ari; Gaulard, Philippe; Mak, Tak W.

doi:10.1016/j.ccell.2023.01.003

Cited by 29 publications

(11 citation statements)

References 58 publications

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“…http://jitc.bmj.com/ Open access after SFN Consistent with previous studies, SFN IL-12RB2, which reduced MMP3 levels, elevated FasL expression to induce the caspase-3 cleavage in MDSCs, and finally induced apoptosis. 53 The role of FasL in MDSCs apoptosis was also reported by Peyvandi et al 54 We verified the role of SFN on MDSCs apoptosis and CD8 + T cells activation in clinical samples. Regarding the safety of SFN, the analysis of the plasma concentrations of liver and kidney profiles showed no differences after SFN treatment.…”

Section: Discussionsupporting

confidence: 85%

“…Consistent with previous studies, SFN stimulated IL-12RB2, which reduced MMP3 levels, elevated FasL expression to induce the caspase-3 cleavage in MDSCs, and finally induced apoptosis. 53 The role of FasL in MDSCs apoptosis was also reported by Peyvandi et al . 54 We verified the role of SFN on MDSCs apoptosis and CD8 + T cells activation in clinical samples.…”

Section: Discussionsupporting

confidence: 58%

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Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Liu,

Chen,

Guo

et al. 2024

J Immunother Cancer

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BackgroundExtensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME).MethodsWe monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8+T cells in the blood samples from a phase I clinical trial (KY-2021–0350).ResultsIn this study, we elucidated that SFN liberated CD8+T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8+T cells.ConclusionsCollectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8+T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 58%

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Liu,

Chen,

Guo

et al. 2024

J Immunother Cancer

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“…Taken together, we can conclude that Dnmt3a mutations partly limit Tfh differentiation, which could negatively impact adaptive immune responses in affected individuals and thus potentially contribute to the suppressed immune responses seen in elderly individuals. Interestingly, recent literature identifies that Tet2 deficiency can lead to the expansion of the Tfh population ( 35-37 ). In other words, the opposite phenotype to what we present here.…”

Section: Discussionmentioning

confidence: 99%

Dnmt3amutations limit normal and autoreactive Tfh differentiation

Shen,

Li,

Boddul

et al. 2024

Preprint

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation, strongly associated with the activity of autoreactive CD4+ T cells.DNMT3Amutations are the most common somatic mutations found in the hematopoietic system of patients with rheumatoid arthritis. However, the role of DNMT3A in CD4+ T cells and CD4+ T follicular helper (Tfh) cells is poorly understood. Since somatic mutations are not identified in standard genome-wide association studies, somatic mutations’ impact on the etiology of diseases could be underestimated. Here, we thoroughly characterized and used the KRN+ splenocyte transfer model of autoimmune joint inflammation and inactivatedDnmt3ausing CRISPR-Cas9 and standard Cre/loxP approaches. Experiments with competitive bone marrow (BM) chimeras identified a positive role forDnmt3ain Tfh differentiation, which was validated by comparing mice withDnmt3amutations in CD4+ cells to animals with WTDnmt3a. In conclusion, We identify thatDnmt3amutations limit normal and autoreactive Tfh differentiation.Key findings–Dnmt3amutations limit Tfh differentiation, which could contribute to reduced immune responses in individuals with somaticDNMT3Amutations.–Deep characterization of the KRN+ splenocyte transfer model defines a dynamic process leading to reproducible autoimmune joint inflammation.–The immuno-CRISPR (iCR) methodology can be used to test the role of candidate genes in disease models.

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“…IDH2 R172 , in particular, appears to be exclusive to nTFHL-AI ( 5 , 27 – 29 ). Furthermore, studies have demonstrated a correlation between IDH2 and the tumor microenvironment (TME) in patients with nTFHL-AI ( 7 , 30 ), suggesting a role for epigenetic mutations in the variation of clinicopathological features. Similarly, nTFHL-F is characterized by distinct ITK-SYK fusion genes ( 31 ) known to induce malignant PTCL ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic analysis of nodal T-follicular helper cell lymphomas, a multicenter retrospective study from China

Ma,

Li,

Zuo

et al. 2024

Front. Immunol.

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BackgroundNodal T-follicular helper cell lymphomas (nTFHLs) represent a new family of peripheral T-cell lymphomas (PTCLs), and comparative studies of their constituents are rare.MethodsThis study retrospectively enrolled 10 patients with nTFHL-F and 30 patients with nTFHL-NOS diagnosed between December 2017 and October 2023 at six large comprehensive tertiary hospitals; 188 patients with nTFHL-AI were diagnosed during the same period at the First Affiliated Hospital of Zhengzhou University for comparison.ResultsCompared with nTFHL-AI, nTFHL-NOS patients exhibited better clinical manifestations, lower TFH expression levels, and a lower Ki-67 index. However, no differences in clinicopathological features were observed between nTFHL-F and nTFHL-AI patients as well as nTFHL-NOS patients. According to the survival analysis, the median OS for patients with nTFHL-NOS, nTFHL-AI, and nTFHL-F were 14.2 months, 10 months, and 5 months, respectively, whereas the median TTP were 14 months, 5 months, and 3 months, respectively. Statistical analysis revealed differences in TTP among the three subtypes(P=0.0173). Among the population of patients receiving CHOP-like induction therapy, there were significant differences in the OS and TTP among the nTFHL-NOS, nTFHL-AI, and nTFHL-F patients (P=0.0134, P=0.0205). Both the GDPT and C-PET regimens significantly improved the ORR, OS, and PFS in nTFHL patients.ConclusionThere are significant differences in the clinical manifestations, pathology, and survival outcomes among the three subtypes of nTFHLs. However, further research with a larger sample size, and involving clinical pathology and molecular genetics is needed to determine the distinctive biological characteristics of these tumors.

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IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment

Cited by 29 publications

References 58 publications

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Dnmt3amutations limit normal and autoreactive Tfh differentiation

Clinicopathologic analysis of nodal T-follicular helper cell lymphomas, a multicenter retrospective study from China

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IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment

Cited by 29 publications

References 58 publications

Sulforaphane activates CD8+T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Sulforaphane activates CD8+T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Dnmt3amutations limit normal and autoreactive Tfh differentiation

Clinicopathologic analysis of nodal T-follicular helper cell lymphomas, a multicenter retrospective study from China

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Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’