Publication Date:
2011-03-26
Description:
Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406187/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406187/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beatty, Gregory L -- Chiorean, Elena G -- Fishman, Matthew P -- Saboury, Babak -- Teitelbaum, Ursina R -- Sun, Weijing -- Huhn, Richard D -- Song, Wenru -- Li, Dongguang -- Sharp, Leslie L -- Torigian, Drew A -- O'Dwyer, Peter J -- Vonderheide, Robert H -- K08 CA138907/CA/NCI NIH HHS/ -- K12 CA076931/CA/NCI NIH HHS/ -- P30 CA016520/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2011 Mar 25;331(6024):1612-6. doi: 10.1126/science.1198443.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21436454" target="_blank"〉PubMed〈/a〉
Keywords:
Adult
;
Aged
;
Animals
;
Antibodies, Monoclonal/administration & dosage/adverse
;
effects/metabolism/*therapeutic use
;
Antigens, CD40/*agonists/*immunology
;
Antineoplastic Agents/administration & dosage/adverse effects/*therapeutic use
;
Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
;
Carcinoma, Pancreatic Ductal/*drug therapy/immunology/pathology/secondary
;
Deoxycytidine/analogs & derivatives/therapeutic use
;
Disease Models, Animal
;
Disease-Free Survival
;
Female
;
Humans
;
Immunologic Surveillance
;
Macrophage Activation
;
Macrophages/immunology
;
Male
;
Mice
;
Middle Aged
;
Pancreatic Neoplasms/*drug therapy/immunology/pathology
;
T-Lymphocytes/immunology
;
Tumor Microenvironment
;
Young Adult
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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