A MYC-LDHA-MCT4 expression program marks an SPP1/TREM2-centered macrophage state in pancreatic ductal adenocarcinoma
- 1Department of Geriatrics, The First Affiliated Hospital of Ningbo University
- 2Department of Emergency Medicine, The First Affiliated Hospital of Ningbo University
Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune-checkpoint blockade, and the metabolic organization of its myeloid barrier is incompletely understood.
Methods: We integrated imaging mass cytometry from the phase II trial NCT04177810, three single-cell RNA-seq datasets, two spatial transcriptomic cohorts (12 sections), three survival cohorts, and in vitro siRNA perturbation of MYC, LDHA and SLC16A3 with conditioned-medium assays on THP-1-derived macrophage-like cells and primary human CD8+ T cells.
Results: CD8+ T-cell infiltration increased without objective responses while macrophages remained abundant. Patient-level epithelial MYC and glycolysis programs correlated with SLC16A3 (MCT4) and a macrophage lactate-reception program. Across 12 spatial sections, macrophage-receiver scores were higher around MCT4-high cores (ring 1: 12/12 positive; median difference 0.433; FDR = 0.010), with the strongest state-resolved signal for SPP1/TREM2 macrophages (median difference 0.613; FDR = 0.006); the composition-adjusted effect remained positive (10/12) but was non-significant (FDR = 0.071). Silencing MYC, LDHA or SLC16A3 reduced extracellular lactate and altered conditioned-medium effects, with partial rescue by lactate add-back. Survival associations were cohort-dependent with substantial heterogeneity.
Discussion: These results define an exploratory, expression-based spatial association between a tumor MYC-LDHA-MCT4 program and an SPP1/TREM2-centered macrophage state, constituting a testable hypothesis rather than evidence of lactate transfer.
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BibTeX
@article{ma2026mycldhamct4,
title = {{A MYC-LDHA-MCT4 expression program marks an SPP1/TREM2-centered macrophage state in pancreatic ductal adenocarcinoma}},
author = {Qianqian Ma and Hequn He and Ting Liu and Ying Li and Chenyang Mao and Chao Shi and Qi Yao},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1978427},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978427/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A MYC-LDHA-MCT4 expression program marks an SPP1/TREM2-centered macrophage state in pancreatic ductal adenocarcinoma
AU - Qianqian Ma
AU - Hequn He
AU - Ting Liu
AU - Ying Li
AU - Chenyang Mao
AU - Chao Shi
AU - Qi Yao
PY - 2026
DA - 2026/10/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1978427
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978427/full
AB - Introduction: Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune-checkpoint blockade, and the metabolic organization of its myeloid barrier is incompletely understood. Methods: We integrated imaging mass cytometry from the phase II trial NCT04177810, three single-cell RNA-seq datasets, two spatial transcriptomic cohorts (12 sections), three survival cohorts, and in vitro siRNA perturbation of MYC, LDHA and SLC16A3 with conditioned-medium assays on THP-1-derived macrophage-like cells and primary human CD8+ T cells. Results: CD8+ T-cell infiltration increased without objective responses while macrophages remained abundant. Patient-level epithelial MYC and glycolysis programs correlated with SLC16A3 (MCT4) and a macrophage lactate-reception program. Across 12 spatial sections, macrophage-receiver scores were higher around MCT4-high cores (ring 1: 12/12 positive; median difference 0.433; FDR = 0.010), with the strongest state-resolved signal for SPP1/TREM2 macrophages (median difference 0.613; FDR = 0.006); the composition-adjusted effect remained positive (10/12) but was non-significant (FDR = 0.071). Silencing MYC, LDHA or SLC16A3 reduced extracellular lactate and altered conditioned-medium effects, with partial rescue by lactate add-back. Survival associations were cohort-dependent with substantial heterogeneity. Discussion: These results define an exploratory, expression-based spatial association between a tumor MYC-LDHA-MCT4 program and an SPP1/TREM2-centered macrophage state, constituting a testable hypothesis rather than evidence of lactate transfer.
SN - 1664-3224
ER -