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
- University of Miami, United States
- University of Nebraska Medical Center, United States
- Sylvester Comprehensive Cancer Center, United States
- The University of Texas Health Science Center at Houston, United States
Abstract
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, Ptf1aCre/+; KrasLSL-G12D/+;Tgfbr2flox/flox (PKT) mice and C57BL/6 mice orthotopically injected with KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1Cre (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).
Data availability
Clinicodemographic data utilized in this analysis can be tracked back to individual patients (e.g., age, CA19-9 values, pathologic response score) despite deidentification. Since these comprise protected health information from human subjects, a limited deidentified dataset with only relevant data to allow reproduction of major findings are provided. All relevant source data from in vitro experiments have also been provided.
Article and author information
Author details
Funding
National Institutes of Health (UL1TR002736)
- Jashodeep Datta
American College of Surgeons (Franklin H. Martin Research Fellowship)
- Jashodeep Datta
Association for Academic Surgery Foundation (Joel J. Roslyn Faculty Award)
- Jashodeep Datta
University of Miami (Stanley Glaser Foundation Award)
- Jashodeep Datta
National Cancer Institute (P30CA240139)
- Nipun B Merchant
- Jashodeep Datta
National Cancer Institute (R01CA161976)
- Nipun B Merchant
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Edna Cukierman, Fox Chase Cancer Center, United States
Ethics
Animal experimentation: This study was strictly performed in agreement with all the recommendations stablished in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal work was performed following the approved Institutional Animal Care and Use Committee (IACUC) protocol (#21-057) of the University of Miami, and supervised by the Division of Veterinary Resources (DVR). All surgical procedures were performed under general anesthesia, analgesic drugs were administered postoperatively, and every effort was made to minimize any form of animal suffering.
Human subjects: -Informed consent was not necessary since tissue sections were accrued previously under a cancer center-wide biospecimen protocol-Institution Review Board /PRMC/site disease group approval for this study was obtained under protocol 20200123
Version history
- Received: March 24, 2022
- Preprint posted: May 5, 2022 (view preprint)
- Accepted: September 13, 2022
- Accepted Manuscript published: September 15, 2022 (version 1)
- Version of Record published: September 26, 2022 (version 2)
Copyright
© 2022, de Castro Silva et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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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
eLife 11:e78921.
https://doi.org/10.7554/eLife.78921
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