Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.05.04.490660

Neutrophil-Mediated Stromal-Tumor 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

de Castro Silva, I.·Sharma, P.·Bianchi, A.·Deshpande, N.·Mehra, S.·England, J.·Hosein, P. J.·Kwon, D.·Merchant, N.·Datta, J.
View original source ↗Export metadata ↓

Abstract

BackgroundPartial/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. MethodsPathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent (case-cohort design). Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils/%lymphocytes) or NLR dynamics during chemotherapy ({Delta}NLR=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, C57BL/6 mice (n=8-10/arm) were orthotopically injected with KrasG12D/+;Trp53fl/+;PdxCre(KPC)cells and randomized to vehicle, NLR-attenuating anti-Ly6G, gemcitabine/paclitaxel, or gemcitabine/paclitaxel+anti-Ly6G treatments. ResultsIn 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (P<0.001) and {Delta}NLR attenuation during NAC (P=0.002) were independently associated with partial/complete pathologic response. An NLR score=pre-chemotherapy NLR+{Delta}NLR 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-1{beta} 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. ConclusionsTherapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1{beta}/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

de Castro Silva, I., Sharma, P., Bianchi, A., Deshpande, N., Mehra, S., England, J., Hosein, P. J., Kwon, D., Merchant, N., Datta, J.. 2022-05-05. Neutrophil-Mediated Stromal-Tumor 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. https://doi.org/10.1101/2022.05.04.490660

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

ATF3 Preserves Macrophage Cholesterol Homeostasis during Metabolic Stress

Background: Macrophages must coordinate immune activation with maintenance of cellular cholesterol homeostasis, yet the transcriptional mechanisms integrating these processes remain incompletely understood. Activating transcription factor 3 (ATF3) suppresses inflammatory and interferon responses and has been implicated in macrophage lipid metabolism, suggesting a role in coordinating immune and sterol-responsive transcriptional programs. Methods: Wild-type and ATF3-deficient bone marrow-derived macrophages were analyzed by bulk RNA sequencing following Toll-like receptor stimulation and under conditions of sterol loading or depletion. Cholesterol content, cytokine production, and sterol-responsive gene expression were quantified. Human metabolic dysfunction-associated steatotic liver disease (MASLD) datasets and Kupffer cell-specific ATF3 knockout mice were used to assess disease relevance in vivo. Results: ATF3 deficiency enhanced inflammatory and interferon-responsive transcriptional programs while suppressing a sterol-responsive gene module enriched for SREBP2 target genes. This phenotype was conserved across diverse Toll-like receptor stimuli and accompanied by persistent Ch25h upregulation. Despite exhibiting elevated cellular cholesterol, ATF3-deficient macrophages retained transcriptional responsiveness to sterol loading and depletion while demonstrating reduced induction of SREBP2-dependent genes across conditions. IFNAR blockade reduced interferon-responsive gene expression but did not normalize Ch25h or sterol-responsive gene expression. In contrast, CRISPR-mediated reduction of Ch25h partially restored sterol-responsive gene expression in inflammatory ATF3-deficient macrophages. In human MASLD, hepatic ATF3 expression positively correlated with disease severity. In mice, ATF3 was preferentially induced in Kupffer cells during metabolic stress, and Kupffer cell-specific deletion of ATF3 increased liver injury and Kupffer cell lipid accumulation. Conclusions: ATF3 supports sterol-responsive transcriptional programs while restraining inflammatory activation in macrophages. ATF3 loss results in elevated cellular cholesterol, impaired SREBP2-dependent gene expression, and persistent derepression of Ch25h, which contributes to but does not fully explain the sterol phenotype. These findings identify ATF3 as a coordinator of macrophage adaptation to inflammatory and metabolic stress and support a protective role for Kupffer cell ATF3 during metabolic liver disease.

immunology↗
bioRxiv2026

Therapeutic anti-IgE antibodies generate distinct functional immune complex signatures

Therapeutic IgG anti-IgE antibodies are benchmarked by their ability to interfere with IgE-Fc[epsilon]RI binding, but their activity within IgE and IgG-containing immune complexes remains poorly defined. Here we show that omalizumab and ligelizumab form binary IgE-IgG and ternary allergen-containing immune complexes with distinct functional properties. In primary human leukocytes, these complexes exhibited antibody- and composition-dependent patterns of cellular association and activation. Using multiplexed focal molography, we resolved Fc receptor engagement across free and complexed antibody states and identified distinct receptor-binding signatures for omalizumab- and ligelizumab-containing complexes. Notably, allergen incorporation reversed the relative ability of the two antibodies to neutralize IgE-Fc[epsilon]RI interactions and remodelled Fc[gamma]R binding. Thus, immune-complex composition is a determinant of therapeutic antibody function.

immunology↗
bioRxiv2026

Proliferation and mutation as humoral immune response

The affinity maturation process, through which antibodies acquire relatively high affinity for an invading pathogen, involves complex mechanisms whose relative importance is not yet fully understood. This study proposes an analytical model of this process, to investigate the main factors governing proliferation and mutation and assess their respective roles. The model suggests that the immune system should not be expected to follow a single, rigid evolutionary pattern, as a wide range of proliferation and mutation strategies can yield nearly optimal outcomes. Keywords: Antibody, antigen, affinity, B-cell, mutation, proliferation

immunology↗