{"id":942,"date":"2025-02-22T11:40:27","date_gmt":"2025-02-22T11:40:27","guid":{"rendered":"http:\/\/elmoustkbal.com\/?p=942"},"modified":"2025-02-22T11:40:27","modified_gmt":"2025-02-22T11:40:27","slug":"the-kinetics-of-increased-treg-frequencies-coincided-with-the-kinetics-of-lymphoma-cell-appearance-in-the-three-tissues-day-8-in-the-lns-day-6-in-bone-marrow-and-spleen-but-not-in-blood","status":"publish","type":"post","link":"https:\/\/elmoustkbal.com\/?p=942","title":{"rendered":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B)"},"content":{"rendered":"

\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B). take advantage of a model of MYC-driven lymphoma to mechanistically dissect the contribution of Tregs to lymphoma pathogenesis and to develop a strategy of Treg-selective interleukin-2 (IL-2) starvation to improve immune control of MYC-driven lymphoma. Results We find that all genetic DLBCL subtypes, except for one characterized by co-occurring mutations, are heavily infiltrated by Tregs. Spectral flow cytometry and scRNA-sequencing reveal the robust expression of functional and immunosuppressive markers on Tregs infiltrating MYC-driven lymphomas; notably, we find that intratumoral Tregs arise due to local conversion from na?ve CD4+ precursors on tumor contact. Treg ablation in Foxp3iDTR mice, or by antibody-mediated Treg-selective blockade of IL-2 signaling, strongly reduces the lymphoma burden. We identify lymphoma B-cells as a major source of IL-2, and show that the effects of Treg depletion are reversed by the simultaneous depletion of Foxp3-negative CD4+ T-cells, but not CD8+ T-cells or natural killer (NK) cells. The inhibition of ATP hydrolyzation and adenosine production by Tregs at least partly phenocopies the effects of Treg depletion. Treg depletion further synergizes with pro-apoptotic CD40 Refametinib (RDEA-119, BAY 86-9766) activation to sustain durable responses. Conclusion The combined data implicate Tregs as a potential therapeutic target in DLBCL, especially in combination with other immunotherapies. Keywords: Hematologic Neoplasms, Immune Evation, Refametinib (RDEA-119, BAY 86-9766)<\/a> Immunologic Surveillance, Immunotherapy, Lymphocytes, Tumor-Infiltrating WHAT IS ALREADY KNOWN ON THIS TOPIC Regulatory T-cells (Tregs) are known to infiltrate lymphomas of the diffuse large B-cell (DLBCL) type, but their role in lymphoma growth and progression has not been studied in experimental models, and the prognostic significance Refametinib (RDEA-119, BAY 86-9766) of Treg infiltration is controversial. WHAT THIS STUDY ADDS We show here that Tregs infiltrating an experimental, MYC-driven lymphoma have characteristics of effector Tregs and differ strongly from their normal thymus-derived counterparts in terms of their immunophenotype and transcriptome. The depletion of Tregs, either in a genetic model or by interleukin-2 (IL-2) starvation, strongly reduces the lymphoma burden, especially when combined with treatments that directly compromise tumor cell viability. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Our study implies that DLBCL that is refractory to standard of care treatments, but infiltrated by large numbers of Tregs, might benefit from experimental Treg-directed therapy, in particular starvation with a Treg-selective IL-2-targeting antibody that is currently in clinical development. Introduction Diffuse large B-cell lymphoma (DLBCL) is an aggressive, highly heterogeneous malignancy derived from mature B-cells that is fatal in a third of Refametinib (RDEA-119, BAY 86-9766) patients. The two major advances in DLBCL treatment were the addition of the CD20-specific antibody rituximab to standard chemotherapy two decades ago1 2 and the recent approval of chimeric antigen receptor (CAR) T-cell therapy for a select group of patients with DLBCL.3 DLBCL originates from antigen-exposed B-cells that have undergone the germinal center (GC) reaction.4 Several molecular subtypes can be distinguished based on transcriptional and mutational signatures, copy number alterations and structural variants.5 6 One of the hallmarks of DLBCL arising in immunocompetent patientsin contrast to post-transplant patients on immunosuppressive therapy7is the mutational inactivation of various genes associated with immune detection and surveillance. Examples include the genes encoding 2-microglobulin and CD58, which are required for cytotoxic T-cell and natural killer (NK) cell recognition and killing of DLBCL cells; both genes are Keratin 8 antibody<\/a> recurrently targeted by deletions, frameshift and other inactivating mutations and their surface expression is compromised in >60% of DLBCL cases.8 Although not directly targeted by mutations, gene expression is abrogated in DLBCL harboring inactivating mutations in the genes encoding the histone acetyltransferases (HATs) CREB binding protein (CREBBP) and EP300; such mutations occur in 30% of DLBCL9 and prevent surface MHCII expression and detection by CD4+ T-cells through loss of the active (acetylated) histone mark on H3K14, H3K18, and H3K27.10C12 Various genetic aberrations lead to programmed death-ligand 1 (PD-L1) overexpression in one-third of DLBCL cases; these include gene amplifications, transcript stabilization by truncation of the 3-UTR and translocations of to the locus.13 14 However, the clinical relevance of PD-L1 overexpression in DLBCL is not clear and trials of PD-1\/PD-L1 blockade in DLBCL have delivered variable results, both as frontline therapy in combination with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in PD-L1 positive patients and as salvage therapy in the setting of relapse after CART19\/20 therapy.15C18 The lymphoma microenvironment of DLBCL has recently received increasing attention as a result of the availability of fluorescent multiplex immunohistochemistry (IHC) and automated quantification technologies, and certain microenvironmental features appear to predict the outcome of patients under R-CHOP therapy.19C21 We focus here on regulatory T-cells (Tregs) as highly variable, possibly predictive.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-942","post","type-post","status-publish","format-standard","hentry","category-t-type-calcium-channels"],"yoast_head":"\n\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B) - DHFR inhibitors in non-small cell lung cancer<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/elmoustkbal.com\/?p=942\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B) - DHFR inhibitors in non-small cell lung cancer\" \/>\n<meta property=\"og:description\" content=\"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6…\" \/>\n<meta property=\"og:url\" content=\"https:\/\/elmoustkbal.com\/?p=942\" \/>\n<meta property=\"og:site_name\" content=\"DHFR inhibitors in non-small cell lung cancer\" \/>\n<meta property=\"article:published_time\" content=\"2025-02-22T11:40:27+00:00\" \/>\n<meta name=\"author\" content=\"webmaster\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"webmaster\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"4 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942\"},\"author\":{\"name\":\"webmaster\",\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/#\\\/schema\\\/person\\\/6ba91697c07f5b1e48a1c50fec2fd4a0\"},\"headline\":\"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B)\",\"datePublished\":\"2025-02-22T11:40:27+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942\"},\"wordCount\":874,\"articleSection\":[\"T-Type Calcium Channels\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942\",\"url\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942\",\"name\":\"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B) - DHFR inhibitors in non-small cell lung cancer\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/#website\"},\"datePublished\":\"2025-02-22T11:40:27+00:00\",\"author\":{\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/#\\\/schema\\\/person\\\/6ba91697c07f5b1e48a1c50fec2fd4a0\"},\"breadcrumb\":{\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/elmoustkbal.com\\\/?p=942\"]}]},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/?p=942#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\\\/\\\/elmoustkbal.com\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B)\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/#website\",\"url\":\"https:\\\/\\\/elmoustkbal.com\\\/\",\"name\":\"DHFR inhibitors in non-small cell lung cancer\",\"description\":\"Just another WordPress site\",\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/elmoustkbal.com\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"},{\"@type\":\"Person\",\"@id\":\"https:\\\/\\\/elmoustkbal.com\\\/#\\\/schema\\\/person\\\/6ba91697c07f5b1e48a1c50fec2fd4a0\",\"name\":\"webmaster\",\"image\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/66fbd3a9ef48c403fd533a73978e5557cc8b799f7e461809e4f768dafe87f404?s=96&d=mm&r=g\",\"url\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/66fbd3a9ef48c403fd533a73978e5557cc8b799f7e461809e4f768dafe87f404?s=96&d=mm&r=g\",\"contentUrl\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/66fbd3a9ef48c403fd533a73978e5557cc8b799f7e461809e4f768dafe87f404?s=96&d=mm&r=g\",\"caption\":\"webmaster\"},\"sameAs\":[\"http:\\\/\\\/elmoustkbal.com\"],\"url\":\"https:\\\/\\\/elmoustkbal.com\\\/?author=1\"}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B) - DHFR inhibitors in non-small cell lung cancer","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/elmoustkbal.com\/?p=942","og_locale":"en_US","og_type":"article","og_title":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B) - DHFR inhibitors in non-small cell lung cancer","og_description":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6…","og_url":"https:\/\/elmoustkbal.com\/?p=942","og_site_name":"DHFR inhibitors in non-small cell lung cancer","article_published_time":"2025-02-22T11:40:27+00:00","author":"webmaster","twitter_card":"summary_large_image","twitter_misc":{"Written by":"webmaster","Est. reading time":"4 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/elmoustkbal.com\/?p=942#article","isPartOf":{"@id":"https:\/\/elmoustkbal.com\/?p=942"},"author":{"name":"webmaster","@id":"https:\/\/elmoustkbal.com\/#\/schema\/person\/6ba91697c07f5b1e48a1c50fec2fd4a0"},"headline":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B)","datePublished":"2025-02-22T11:40:27+00:00","mainEntityOfPage":{"@id":"https:\/\/elmoustkbal.com\/?p=942"},"wordCount":874,"articleSection":["T-Type Calcium Channels"],"inLanguage":"en-US"},{"@type":"WebPage","@id":"https:\/\/elmoustkbal.com\/?p=942","url":"https:\/\/elmoustkbal.com\/?p=942","name":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B) - DHFR inhibitors in non-small cell lung cancer","isPartOf":{"@id":"https:\/\/elmoustkbal.com\/#website"},"datePublished":"2025-02-22T11:40:27+00:00","author":{"@id":"https:\/\/elmoustkbal.com\/#\/schema\/person\/6ba91697c07f5b1e48a1c50fec2fd4a0"},"breadcrumb":{"@id":"https:\/\/elmoustkbal.com\/?p=942#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/elmoustkbal.com\/?p=942"]}]},{"@type":"BreadcrumbList","@id":"https:\/\/elmoustkbal.com\/?p=942#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/elmoustkbal.com\/"},{"@type":"ListItem","position":2,"name":"\ufeffThe kinetics of increased Treg frequencies coincided with the kinetics of lymphoma cell appearance in the three tissues (day 8 in the LNs, day 6 in bone marrow and spleen), but not in blood, where only modest Treg increases were visible, and only with a 3-day delay at day 9 (figure 5A,B, online supplemental figure S4A,B)"}]},{"@type":"WebSite","@id":"https:\/\/elmoustkbal.com\/#website","url":"https:\/\/elmoustkbal.com\/","name":"DHFR inhibitors in non-small cell lung cancer","description":"Just another WordPress site","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/elmoustkbal.com\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"},{"@type":"Person","@id":"https:\/\/elmoustkbal.com\/#\/schema\/person\/6ba91697c07f5b1e48a1c50fec2fd4a0","name":"webmaster","image":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/secure.gravatar.com\/avatar\/66fbd3a9ef48c403fd533a73978e5557cc8b799f7e461809e4f768dafe87f404?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/66fbd3a9ef48c403fd533a73978e5557cc8b799f7e461809e4f768dafe87f404?s=96&d=mm&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/66fbd3a9ef48c403fd533a73978e5557cc8b799f7e461809e4f768dafe87f404?s=96&d=mm&r=g","caption":"webmaster"},"sameAs":["http:\/\/elmoustkbal.com"],"url":"https:\/\/elmoustkbal.com\/?author=1"}]}},"_links":{"self":[{"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=\/wp\/v2\/posts\/942","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=942"}],"version-history":[{"count":1,"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=\/wp\/v2\/posts\/942\/revisions"}],"predecessor-version":[{"id":943,"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=\/wp\/v2\/posts\/942\/revisions\/943"}],"wp:attachment":[{"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=942"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=942"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/elmoustkbal.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=942"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}