دورية أكاديمية
أعرض في EDS

Neutrophil-mediated fibroblast-tumor cell il-6/stat-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study.

التفاصيل البيبلوغرافية
العنوان: Neutrophil-mediated fibroblast-tumor cell il-6/stat-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study.
المؤلفون: de Castro Silva I; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States., Bianchi A; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States., Deshpande NU; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States., Sharma P; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States.; Department of Surgery, University of Nebraska Medical Center, Omaha, United States., Mehra S; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States., Garrido VT; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States., Saigh SJ; Sylvester Comprehensive Cancer Center, Miami, United States., England J; Department of Pathology, University of Miami, Miami, United States., Hosein PJ; Sylvester Comprehensive Cancer Center, Miami, United States.; Department of Medicine, University of Miami, Miami, United States., Kwon D; Department of Public Health Sciences, The University of Texas Health Science Center at Houston, Houston, United States., Merchant NB; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States.; Department of Public Health Sciences, The University of Texas Health Science Center at Houston, Houston, United States., Datta J; Department of Surgery, University of Miami Miller School of Medicine, Miami, United States.; Department of Public Health Sciences, The University of Texas Health Science Center at Houston, Houston, United States.
المصدر: ELife [Elife] 2022 Sep 15; Vol. 11. Date of Electronic Publication: 2022 Sep 15.
نوع المنشور: Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Carcinoma, Pancreatic Ductal*/pathology , Pancreatic Neoplasms*/drug therapy , Pancreatic Neoplasms*/pathology, Animals ; CD8-Positive T-Lymphocytes ; Fibroblasts/pathology ; Humans ; Interleukin-6 ; Lymphocytes/pathology ; Mice ; Mice, Inbred C57BL ; Neutrophils/pathology ; Paclitaxel/therapeutic use ; Proto-Oncogene Proteins p21(ras) ; Receptor, Transforming Growth Factor-beta Type II
مستخلص: Background: Partial/complete pathologic response following neoadjuvant chemotherapy (NAC) in pancreatic cancer (PDAC) patients undergoing pancreatectomy is associated with improved survival. We sought to determine whether neutrophil-to-lymphocyte ratio (NLR) dynamics predict pathologic response following chemotherapy in PDAC, and if manipulating NLR impacts chemosensitivity in preclinical models and uncovers potential mechanistic underpinnings underlying these effects.
Methods: Pathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent. Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils÷%lymphocytes) or NLR dynamics during chemotherapy (ΔNLR = pre-surgery-pre-chemotherapy NLR) and pathologic response, disease-free survival (DFS), and overall survival (OS). To preclinically model effects of NLR attenuation on chemosensitivity, Ptf1a Cre/+ ; Kras LSL-G12D/+ ;Tgfbr2 flox/flox (PKT) mice and C57BL/6 mice orthotopically injected with Kras LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Pdx1 Cre (KPC) cells were randomized to vehicle, gemcitabine/paclitaxel alone, and NLR-attenuating anti-Ly6G with/without gemcitabine/paclitaxel treatment.
Results: In 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (p<0.001) and ΔNLR attenuation during NAC (p=0.002) were independently associated with partial/complete pathologic response. An NLR score = pre-chemotherapy NLR+ΔNLR correlated with DFS (p=0.006) and OS (p=0.002). Upon preclinical modeling, combining NLR-attenuating anti-Ly6G treatment with gemcitabine/paclitaxel-compared with gemcitabine/paclitaxel or anti-Ly6G alone-not only significantly reduced tumor burden and metastatic outgrowth, but also augmented tumor-infiltrating CD107a + -degranulating CD8 + T-cells (p<0.01) while dampening inflammatory cancer-associated fibroblast (CAF) polarization (p=0.006) and chemoresistant IL-6/STAT-3 signaling in vivo. Neutrophil-derived IL-1β emerged as a novel mediator of stromal inflammation, inducing inflammatory CAF polarization and CAF-tumor cell IL-6/STAT-3 signaling in ex vivo co-cultures.
Conclusions: Therapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC.
Funding: Supported by KL2 career development grant by Miami CTSI under NIH Award UL1TR002736, Stanley Glaser Foundation, American College of Surgeons Franklin Martin Career Development Award, and Association for Academic Surgery Joel J. Roslyn Faculty Award (to J. Datta); NIH R01 CA161976 (to N.B. Merchant); and NCI/NIH Award P30CA240139 (to J. Datta and N.B. Merchant).
Competing Interests: Id, AB, ND, PS, SM, VG, SS, JE, PH, DK, NM, JD No competing interests declared
(© 2022, de Castro Silva et al.)
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معلومات مُعتمدة: P30 CA240139 United States CA NCI NIH HHS; R01 CA161976 United States CA NCI NIH HHS; UL1 TR002736 United States TR NCATS NIH HHS
فهرسة مساهمة: Keywords: cancer associated fibroblasts; chemotherapy resistance; human; immunology; inflammation; medicine; mouse; myeloid-derived suppressor cells (MDSCs); neutrophils; pancreas cancer; surgery
المشرفين على المادة: 0 (Interleukin-6)
EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type II)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
P88XT4IS4D (Paclitaxel)
تواريخ الأحداث: Date Created: 20220915 Date Completed: 20220928 Latest Revision: 20240517
رمز التحديث: 20240517
مُعرف محوري في PubMed: PMC9512403
DOI: 10.7554/eLife.78921
PMID: 36107485
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.78921