{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:13:46Z","timestamp":1782969226778,"version":"3.54.5"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI, or AITL), is an aggressive peripheral T cell lymphoma without effective treatments. It has been shown that genetic and epigenetic changes lead to the expansion of neoplastic CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells originating from T follicular helper (Tfh) cells, which subsequently cause B cell expansion and tumor development. However, it remains unclear if the Tfh-like cell populations contain a subset that drives tumor progression and, if so, whether such a subset may have druggable targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Through single-cell transcriptome analysis of Tfh-like cells isolated from the spontaneously arising AITL-like tumors in\n                      <jats:italic>\n                        Roquin\n                        <jats:sup>san\/+<\/jats:sup>\n                      <\/jats:italic>\n                      mice, we identified and characterized a tumor-enriched Tfh cell subset highly expressing CXCR6 and IL-18 receptor, termed \u201cDouble-Expressor (DE) Tfh\u201d cells. Using genetic or pharmacological approaches, we depleted DE Tfh cells\n                      <jats:italic>in vivo<\/jats:italic>\n                      and monitored tumor size (by ultrasound imaging) and the status of DE Tfh subset (by flow cytometry). We performed NanoString gene expression profiling of AITL patient samples to identify AITL cases that are relevant to\n                      <jats:italic>\n                        Roquin\n                        <jats:sup>san\/+<\/jats:sup>\n                      <\/jats:italic>\n                      mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DE Tfh cells expressed higher levels of Ki-67 and enhancer of zeste homolog 2 (EZH2) and proliferated more rapidly compared to other Tfh cells in an IL-18 and EZH2 dependent manner. Furthermore, DE Tfh cells engrafted better than non-DE Tfh cells and could cause B cell expansion when adoptively transferred into lymphopenic recipients. On the other hand, depletion of DE Tfh cells via\n                      <jats:italic>Ezh2<\/jats:italic>\n                      gene deletion, inhibition of EZH2 (using FDA-approved drug, tazemetostat), or anti-CXCR6 mAb led to tumor regression. These findings may be relevant to a subset of human AITL cases since we found that ~20-30% of AITL patient samples have concomitantly elevated expression of\n                      <jats:italic>CXCR6<\/jats:italic>\n                      ,\n                      <jats:italic>IL-18R1<\/jats:italic>\n                      , and\n                      <jats:italic>IFNG<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identified a pathogenic Tfh-like subset essential for AITL tumor progression in a mouse model and suggests that identifying and targeting a DE Tfh-like subset in AITL patients might be an effective strategy.<\/jats:p>\n                  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