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T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions
The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However,...
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| Published in: | The Journal of clinical investigation 2025-01, Vol.135 (1) |
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| container_title | The Journal of clinical investigation |
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| creator | Oka, Tomonori Smith, Sabrina S Son, Heehwa G Lee, Truelian Oliver-Garcia, Valeria S Mortaja, Mahsa Trerice, Kathryn E Isakoff, Lily S Conrad, Danielle N Azin, Marjan Raval, Neel S Tabacchi, Mary Emdad, Luni Das, Swadesh K Fisher, Paul B Cornelius, Lynn A Demehri, Shadmehr |
| description | The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy. |
| doi_str_mv | 10.1172/JCI183274 |
| format | article |
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Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI183274</identifier><identifier>PMID: 39744942</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animals ; Apoptosis ; B cells ; Calcipotriene ; Calcitriol - administration & dosage ; Calcitriol - analogs & derivatives ; Calcitriol - pharmacology ; Cancer ; Carcinoma, Squamous Cell - immunology ; Carcinoma, Squamous Cell - pathology ; Carcinoma, Squamous Cell - therapy ; Cytokines ; Cytokines - immunology ; Cytokines - metabolism ; Development and progression ; Fluorouracil - administration & dosage ; Fluorouracil - therapeutic use ; Health aspects ; Humans ; Immunotherapy ; Interleukins - genetics ; Interleukins - immunology ; Keratinocytes - immunology ; Keratinocytes - pathology ; Mice ; Precancerous Conditions - immunology ; Precancerous Conditions - pathology ; Precancerous Conditions - prevention & control ; Precancerous Conditions - therapy ; Prevention ; Skin ; Skin cancer ; Skin lesions ; Skin Neoplasms - immunology ; Skin Neoplasms - pathology ; Skin Neoplasms - therapy ; Squamous cell carcinoma ; Th2 Cells - immunology</subject><ispartof>The Journal of clinical investigation, 2025-01, Vol.135 (1)</ispartof><rights>COPYRIGHT 2025 American Society for Clinical Investigation</rights><rights>2025 Oka et al. 2025 Oka et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3481-8830f41c459fa1119bc84d02d464e59f58e4bae0f71b68d2d7cbaf6f7dac265c3</cites><orcidid>0000-0002-7913-2641</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39744942$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oka, Tomonori</creatorcontrib><creatorcontrib>Smith, Sabrina S</creatorcontrib><creatorcontrib>Son, Heehwa G</creatorcontrib><creatorcontrib>Lee, Truelian</creatorcontrib><creatorcontrib>Oliver-Garcia, Valeria S</creatorcontrib><creatorcontrib>Mortaja, Mahsa</creatorcontrib><creatorcontrib>Trerice, Kathryn E</creatorcontrib><creatorcontrib>Isakoff, Lily S</creatorcontrib><creatorcontrib>Conrad, Danielle N</creatorcontrib><creatorcontrib>Azin, Marjan</creatorcontrib><creatorcontrib>Raval, Neel S</creatorcontrib><creatorcontrib>Tabacchi, Mary</creatorcontrib><creatorcontrib>Emdad, Luni</creatorcontrib><creatorcontrib>Das, Swadesh K</creatorcontrib><creatorcontrib>Fisher, Paul B</creatorcontrib><creatorcontrib>Cornelius, Lynn A</creatorcontrib><creatorcontrib>Demehri, Shadmehr</creatorcontrib><title>T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>B cells</subject><subject>Calcipotriene</subject><subject>Calcitriol - administration & dosage</subject><subject>Calcitriol - analogs & derivatives</subject><subject>Calcitriol - pharmacology</subject><subject>Cancer</subject><subject>Carcinoma, Squamous Cell - immunology</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Carcinoma, Squamous Cell - therapy</subject><subject>Cytokines</subject><subject>Cytokines - immunology</subject><subject>Cytokines - metabolism</subject><subject>Development and progression</subject><subject>Fluorouracil - administration & dosage</subject><subject>Fluorouracil - therapeutic use</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Interleukins - genetics</subject><subject>Interleukins - immunology</subject><subject>Keratinocytes - immunology</subject><subject>Keratinocytes - pathology</subject><subject>Mice</subject><subject>Precancerous Conditions - immunology</subject><subject>Precancerous Conditions - pathology</subject><subject>Precancerous Conditions - prevention & control</subject><subject>Precancerous Conditions - therapy</subject><subject>Prevention</subject><subject>Skin</subject><subject>Skin cancer</subject><subject>Skin lesions</subject><subject>Skin Neoplasms - immunology</subject><subject>Skin Neoplasms - pathology</subject><subject>Skin Neoplasms - therapy</subject><subject>Squamous cell carcinoma</subject><subject>Th2 Cells - immunology</subject><issn>1558-8238</issn><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNqNkl2L1DAUhoso7ode-AekIMh60TVp0ja9WpbBj9GFBV29DWlyMo2mSU1Scf-9GXYdZmAvJBcJJ8954bznLYoXGJ1j3NVvP63WmJG6o4-KY9w0rGI1YY_33kfFSYw_EMKUNvRpcUT6jtKe1sfF55tyBDtDKOtSgrWVMgFkAlWaaVqcTyMEMd-WYM1knEgQyzkDwkkIfoll_GlcaSEa7-Kz4okWNsLz-_u0-Pb-3c3qY3V1_WG9uryqJKEMV4wRpCmWtOm1wBj3g2RUoVrRlkKuNQzoIADpDg8tU7Xq5CB0qzslZN02kpwWF3e68zJMoCS4FITlczCTCLfcC8MPf5wZ-cb_5hi3jDKEssLZvULwvxaIiU8mbscXDvJUnOAGMcI6QjP66g7dCAvcOO2zpNzi_DJb27dt0-BMnT9A5aNgMtI70CbXDxreHDRkJsGftBFLjHz99cv_s9ffD9nXe-wIwqYxeruk7YIeFJXBxxhA7_zDiG9TxXepyuzLfcN35L8Ykb_m38Sk</recordid><startdate>20250102</startdate><enddate>20250102</enddate><creator>Oka, Tomonori</creator><creator>Smith, Sabrina S</creator><creator>Son, Heehwa G</creator><creator>Lee, Truelian</creator><creator>Oliver-Garcia, Valeria S</creator><creator>Mortaja, Mahsa</creator><creator>Trerice, Kathryn E</creator><creator>Isakoff, Lily S</creator><creator>Conrad, Danielle N</creator><creator>Azin, Marjan</creator><creator>Raval, Neel S</creator><creator>Tabacchi, Mary</creator><creator>Emdad, Luni</creator><creator>Das, Swadesh K</creator><creator>Fisher, Paul B</creator><creator>Cornelius, Lynn A</creator><creator>Demehri, Shadmehr</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7913-2641</orcidid></search><sort><creationdate>20250102</creationdate><title>T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions</title><author>Oka, Tomonori ; Smith, Sabrina S ; Son, Heehwa G ; Lee, Truelian ; Oliver-Garcia, Valeria S ; Mortaja, Mahsa ; Trerice, Kathryn E ; Isakoff, Lily S ; Conrad, Danielle N ; Azin, Marjan ; Raval, Neel S ; Tabacchi, Mary ; Emdad, Luni ; Das, Swadesh K ; Fisher, Paul B ; Cornelius, Lynn A ; Demehri, Shadmehr</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3481-8830f41c459fa1119bc84d02d464e59f58e4bae0f71b68d2d7cbaf6f7dac265c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>B cells</topic><topic>Calcipotriene</topic><topic>Calcitriol - administration & dosage</topic><topic>Calcitriol - analogs & derivatives</topic><topic>Calcitriol - pharmacology</topic><topic>Cancer</topic><topic>Carcinoma, Squamous Cell - immunology</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Carcinoma, Squamous Cell - therapy</topic><topic>Cytokines</topic><topic>Cytokines - immunology</topic><topic>Cytokines - metabolism</topic><topic>Development and progression</topic><topic>Fluorouracil - administration & dosage</topic><topic>Fluorouracil - therapeutic use</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Interleukins - genetics</topic><topic>Interleukins - immunology</topic><topic>Keratinocytes - immunology</topic><topic>Keratinocytes - pathology</topic><topic>Mice</topic><topic>Precancerous Conditions - immunology</topic><topic>Precancerous Conditions - pathology</topic><topic>Precancerous Conditions - prevention & control</topic><topic>Precancerous Conditions - therapy</topic><topic>Prevention</topic><topic>Skin</topic><topic>Skin cancer</topic><topic>Skin lesions</topic><topic>Skin Neoplasms - immunology</topic><topic>Skin Neoplasms - pathology</topic><topic>Skin Neoplasms - therapy</topic><topic>Squamous cell carcinoma</topic><topic>Th2 Cells - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oka, Tomonori</creatorcontrib><creatorcontrib>Smith, Sabrina S</creatorcontrib><creatorcontrib>Son, Heehwa G</creatorcontrib><creatorcontrib>Lee, Truelian</creatorcontrib><creatorcontrib>Oliver-Garcia, Valeria S</creatorcontrib><creatorcontrib>Mortaja, Mahsa</creatorcontrib><creatorcontrib>Trerice, Kathryn E</creatorcontrib><creatorcontrib>Isakoff, Lily S</creatorcontrib><creatorcontrib>Conrad, Danielle N</creatorcontrib><creatorcontrib>Azin, Marjan</creatorcontrib><creatorcontrib>Raval, Neel S</creatorcontrib><creatorcontrib>Tabacchi, Mary</creatorcontrib><creatorcontrib>Emdad, Luni</creatorcontrib><creatorcontrib>Das, Swadesh K</creatorcontrib><creatorcontrib>Fisher, Paul B</creatorcontrib><creatorcontrib>Cornelius, Lynn A</creatorcontrib><creatorcontrib>Demehri, Shadmehr</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oka, Tomonori</au><au>Smith, Sabrina S</au><au>Son, Heehwa G</au><au>Lee, Truelian</au><au>Oliver-Garcia, Valeria S</au><au>Mortaja, Mahsa</au><au>Trerice, Kathryn E</au><au>Isakoff, Lily S</au><au>Conrad, Danielle N</au><au>Azin, Marjan</au><au>Raval, Neel S</au><au>Tabacchi, Mary</au><au>Emdad, Luni</au><au>Das, Swadesh K</au><au>Fisher, Paul B</au><au>Cornelius, Lynn A</au><au>Demehri, Shadmehr</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2025-01-02</date><risdate>2025</risdate><volume>135</volume><issue>1</issue><issn>1558-8238</issn><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>39744942</pmid><doi>10.1172/JCI183274</doi><orcidid>https://orcid.org/0000-0002-7913-2641</orcidid><oa>free_for_read</oa></addata></record> |
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| source | EZB Electronic Journals Library |
| subjects | Animals Apoptosis B cells Calcipotriene Calcitriol - administration & dosage Calcitriol - analogs & derivatives Calcitriol - pharmacology Cancer Carcinoma, Squamous Cell - immunology Carcinoma, Squamous Cell - pathology Carcinoma, Squamous Cell - therapy Cytokines Cytokines - immunology Cytokines - metabolism Development and progression Fluorouracil - administration & dosage Fluorouracil - therapeutic use Health aspects Humans Immunotherapy Interleukins - genetics Interleukins - immunology Keratinocytes - immunology Keratinocytes - pathology Mice Precancerous Conditions - immunology Precancerous Conditions - pathology Precancerous Conditions - prevention & control Precancerous Conditions - therapy Prevention Skin Skin cancer Skin lesions Skin Neoplasms - immunology Skin Neoplasms - pathology Skin Neoplasms - therapy Squamous cell carcinoma Th2 Cells - immunology |
| title | T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions |
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