[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-405845-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-405845-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","heparin-prowess-favorable-vascularimmune-reprogramming-in-pancreatic-cancer","Heparin Prowess - Favorable Vascular–Immune Reprogramming in Pancreatic Cancer","","Clinical Cancer Research evaluates how heparin can counter immunotherapy resistance in pancreatic and colorectal cancer syngeneic mouse models. Low molecular weight heparin combined with adoptive cell transfer or anti–PD-1 markedly improved outcomes versus heparin alone, including correction of hypercoagulability, reduced aberrant angiogenesis, deeper CD8+ T-cell infiltration, and macrophage polarization toward an antitumor M1 state. Effects included fewer FOXP3+ Tregs, slower tumor growth, suppressed metastasis in orthotopic pancreatic models, and prolonged 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did heparin change the effect of immunotherapy in pancreatic cancer models?","Question",{"text":63,"@type":64},"Heparin combined with ACT or anti–PD-1 produced beneficial effects not seen with heparin alone, including better tumor control and immune remodeling in the tumor microenvironment.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Which immune and vascular changes were linked to improved responses?",{"text":68,"@type":64},"The paper attributes improvements to vascular normalization, increased CD8+ T-cell infiltration, and macrophage polarization toward an M1-protective phenotype, alongside reduced Treg-mediated immunosuppression.",{"name":70,"@type":61,"acceptedAnswer":71},"Did heparin directly alter immune checkpoint markers?",{"text":72,"@type":64},"The document reports that heparin did not significantly alter PD-1 or CD69 expression in immune cells, suggesting limited direct modulation of immune cell 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\nSeveral approaches for overcoming immunotherapy resistance in pancreatic and colorectal cancer syngeneic models were assessed using heparin and immunotherapy. Beneficial responses were attributed to heparin-induced vascular normalization, ensuing  \nCD8þ T-cell infiltration, and M1macrophage polarization, suggesting the potential for heparin-anchored therapies in cold tumors such as pancreatic cancer.  \nSee related article by Wei et al., p. 2525  \nIn this issue of Clinical Cancer Research, Wei and colleagues (1) combined low molecular weight heparin (LMWH) with either adoptive cell transfer (ACT) or an anti–programmed cell death protein 1 (PD-1) checkpoint inhibitor in syngeneic mouse models of pancreatic cancer and colorectal cancer. Three distinct cell lines were used. The Panc02 murine pancreatic cancer cell (PCC) line yielded immune desert (cold) tumors, the MC38 murine colorectal cancer cells formed inflamed (hot) tumors, whereas the CT26 colorectal cancer murine cells generated immunologically intermediate immune-excluded tumors. LMWH alone did not alter subcutaneous tumor growth of any of these cell lines, and did not affect the growth of orthotopically implanted Panc02 cells. ACT, using spleen-derived lymphocytes that were activated with IL2 and concanavalin A, yielded modest results. In contrast, the combination of LMWH with either ACT or an anti—PD- 1 antibody exerted beneficial effects that included elimination of a hypercoagulable state, suppression of aberrant angiogenesis with improved blood flow, enhanced penetration of CD8þ T cells into the tumor microenvironment (TME), reprogramming of M2 deleterious macrophages into M1-protective macrophages, a decrease in FOXP3þ T-regulatory(Treg) cells, attenuated tumor growth, suppressed metastasisin the orthotopic pancreatic cancer model, and prolonged survival in mice with orthotopic pancreatic cancer tumors 9 (Fig. 1) .  \nPretreatment, in the subcutaneous models, there were foci of tumor necrosis, leakyblood vessels, and emboli, all ofwhich were most evident in immune desert and excluded tumors where LWMH mitigated their formation without promoting CD8þ T-cell infiltration. In contrast, in the inflamed tumors, LMWH increased the number of CD8þ T cells. Wei and colleagues (1) tested the hypothesis that combining ACT with LMWH will not only eliminate the coagulopathy in the Panc02 immune desert tumors and CT26 immune excluded tumors, but will also enhance CD8þ T-cell tumor infiltration. That is exactly what they observed. Moreover, using multiplex histochemistry they demonstrated that there was a concomitant increase in CD8þ/PD-1þ T cells, representing a subpopulation of recently activated and immunologically robust pool of CD8þ T cells. In contrast, the number of  \nDepartment of Developmental and Cell Biology, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California.  \nCorresponding Author: Murray Korc, Department of Developmental and Cell Biology, University of California, Irvine, Irvine, [CA 92697. E-mail: mkorc@uci.edu](CA 92697. E-mail: mkorc@uci.edu)[ ](CA 92697. E-mail: mkorc@uci.edu)[Clin Cancer Res 2023](Clin Cancer Res 2023);[29:2348](29:2348)–[50](50)  \n[doi:](doi: 10.1158/1078-0432.CCR-23-0346)[ 10.1158/1078-0432.CCR-23-0346](doi: 10.1158/1078-0432.CCR-23-0346)  \nThis open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4 . 0 International (CC BY-NC-ND 4 . 0) license.  \n􀀁2023The Authors;Published by the American Association for Cancer Research  \nMHC class II–restricted CD4þ T cells did not increase. Using HALO analysis,theyalso showedthattherewas a decreaseinthe number ofTreg cells in the subcutaneous models both at the tumor edge and its center, suggesting a blunting of Treg cell–mediated immunosuppression.  \nMacrophages are an important component of the TME (2), and Wei and colleagues (1)","cbCaiaoZsi5ws8XR","https://ap.wps.com/l/cbCaiaoZsi5ws8XR","pdf",1214302,"English","# Background\n## Experimental combinations and tumor models\n# Key mechanisms\n## Vascular normalization and T-cell infiltration\n## Macrophage polarization and Treg reduction\n# Therapeutic outcomes\n## Tumor growth, metastasis, and survival","[{\"question\":\"How did heparin change the effect of immunotherapy in pancreatic cancer models?\",\"answer\":\"Heparin combined with ACT or anti–PD-1 produced beneficial effects not seen with heparin alone, including better tumor control and immune remodeling in the tumor microenvironment.\"},{\"question\":\"Which immune and vascular changes were linked to improved responses?\",\"answer\":\"The paper attributes improvements to vascular normalization, increased CD8+ T-cell infiltration, and macrophage polarization toward an M1-protective phenotype, alongside reduced Treg-mediated immunosuppression.\"},{\"question\":\"Did heparin directly alter immune checkpoint markers?\",\"answer\":\"The document reports that heparin did not significantly alter PD-1 or CD69 expression in immune cells, suggesting limited direct modulation of immune cell function.\"}]","Heparin Prowess - Favorable Vascular–Immune Reprogramming in Pancreatic Cancer | PDF",1790562089]