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. 2024 Jun;130(12):1979-1989.
doi: 10.1038/s41416-024-02676-w. Epub 2024 Apr 20.

Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma

Hyung Keun Lee  1   2   3 , So Young Kim  1   4 , Soo-Hyun Chung  5   6 , Bongkun Choi  5   6 , Ji-Eun Kim  5   6 , Dohee Yoon  5   6 , Sung Ill Jang  7 , Areum Yeo  1   4 , Hyun Goo Kang  2 , Jusung Lee  8   9 , Yoon Ha Choi  8 , Joon Seong Park  10   11 , Yoolim Sung  5   6 , Jong Kyoung Kim #  12   13 , Eun-Ju Chang #  14   15 , Dong Ki Lee #  16
Affiliations

Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma

Hyung Keun Lee et al. Br J Cancer. 2024 Jun.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor survival rate, largely due to the lack of early diagnosis. Although myeloid cells are crucial in the tumour microenvironment, whether their specific subset can be a biomarker of PDAC progression is unclear.

Methods: We analysed IL-22 receptor expression in PDAC and peripheral blood. Additionally, we analysed gene expression profiles of IL-10R2+/IL-22R1+ myeloid cells and the presence of these cells using single-cell RNA sequencing and murine orthotropic PDAC models, respectively, followed by examining the immunosuppressive function of IL-10R2+/IL-22R1+ myeloid cells. Finally, the correlation between IL-10R2 expression and PDAC progression was evaluated.

Results: IL-10R2+/IL-22R1+ myeloid cells were present in PDAC and peripheral blood. Blood IL-10R2+ myeloid cells displayed a gene expression signature associated with tumour-educated circulating monocytes. IL-10R2+/IL-22R1+ myeloid cells from human myeloid cell culture inhibited T cell proliferation. By mouse models for PDAC, we found a positive correlation between pancreatic tumour growth and increased blood IL-10R2+/IL-22R1+ myeloid cells. IL-10R2+/IL-22R1+ myeloid cells from an early phase of the PDAC model suppressed T cell proliferation and cytotoxicity. IL-10R2+ myeloid cells indicated tumour recurrence 130 days sooner than CA19-9 in post-pancreatectomy patients.

Conclusions: IL-10R2+/IL-22R1+ myeloid cells in the peripheral blood might be an early marker of PDAC prognosis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Concomitant elevation in IL-22 in PDAC and IL-10R2+/IL-22R1+ cells in PDAC patient peripheral blood.
a Pie charts represent the fractions of IL-10 family cytokines (ST: strong, INT: intermittent, NEG: negative staining), as evaluated by TMAs from PDAC patients (n = 184). b Gene expression levels of receptors that bind to IL-10 cytokines were analysed by qPCR from naïve (CTL) and PDAC PBMCs. qPCR experiments were repeated three times with triplicate samples (mean ± SD, **p < 0.01; ***p < 0.001; Student t-test). (c, d) Comparison of the expression of IL-22+, IL-10R2+ or IL-22R1+CD45+ cells in PBMCs under nontumorous (c) or tumorous conditions of the pancreas (d) by flow cytometry (one-way ANOVA with Tukey’s post hoc multiple comparison tests; each p-value for each disease were compared with PDAC; NS: not significant). CTL; control (n = 98), AP; acute pancreatitis (n = 25), CP; chronic pancreatitis (n = 36), AIAP; alcohol-induced acute pancreatitis (n = 13), Cho; cholangitis (n = 52), CBDS; common bile duct stone (n = 31), GBS; gall bladder stone (n = 42), PDAC; pancreatic ductal adenocarcinoma (n = 180), AoVCa; ampulla of Vater carcinoma (n = 5), BCA; biliary carcinoma (n = 91), NET; neuroendocrine tumour of the pancreas (n = 6), PC; pancreatic cyst or pseudocysts (n = 23), LC; lung cancer (n = 15), CoCa; colon cancer (N = 15), IPMN; intraductal papillary mucinous neoplasm (N = 13).
Fig. 2
Fig. 2. Characterisation of IL-10R2+ cells in PDAC patients’ blood by scRNA-seq, and their infiltration in PDAC and an immunosuppressive function.
a UMAP plots of 24,819 IL-10R2+ PBMCs for five patients (P1–5) with PDAC and of 3,721 IL-10R2- PBMCs for one patient with PDAC as a control (P5[−]). b UMAP plots of immune cell type. c Immune cell-type distribution for 33,981 PBMCs from five healthy donors (N1–5), 3721 IL-10R2- PMBCs from one PDAC patient (P5[−]) and 18,608 IL-10R2+ PBMCs from five PDAC patients (P1–5). d Cell subtype distribution of PBMCs within the mono/macrophage compartment with CD14 and CD16. e Violin plots show TEM signature scores for the monocyte/macrophage compartment in controls and PDAC patients (left), as well as in IL-10R2− (P5[−]) and IL-10R2+ (P5) PBMCs from PDAC patients (right) (***p < 10−8 using the Wilcoxon rank sum test). f Violin plots showing TEM signature scores for the monocyte/macrophage compartment in CD14+ and CD16+ subtypes of IL-10R2+ PBMCs from PDAC patients (***p < 2.2 × 10−16 using the Wilcoxon rank sum test). g FACS analysis strategies for human PDAC tissue samples. PDAC cells were gated on lymphocytes (CD45+), and IL-22R1 and IL-10R2 expression was presented. h IL-22R1+ CD45+ (left), IL-10R2+CD45+ (middle) and IL-22R1+IL-10R2+ CD45+ (right) cell numbers between normal (normal) and PDAC pancreatic tissue (n = 6) were determined by flow cytometry (Mann-Whitney U test). i IL-22R1, IL-10R2 expression on human PBMCs (left) or MDSC culture (GM-CSF + IL-6, right) were determined by flow cytometry. j IL-10R2- and IL-22R1-expressing cells were sorted from the MDSC culture, and T cell proliferation was examined in coculture of myeloid cells and T cells. Means and SDs of triplicate culture were presented. *p < 0.05, **p < 0.01, ***p < 0.001 by students’ t-test.
Fig. 3
Fig. 3. Enrichment of IL-10R2+ myeloid cells infiltrating tumour tissues and immunosuppressive functions during pancreatic tumour progression in murine models.
a A mouse PDAC model was created by orthotopic injection of Pan02 cells into the pancreas of C57BL/6 mice. Four mice each on days 0, 3 and 7 were sacrificed, and blood cells, pancreatic tissue or tumour cells were analysed. b Gating strategy for flow cytometry analysis. The cells were gated by front/side scatters and further on singlets (FSC-A and FSC-H), lymphocytes (CD45+), followed by analysing IL-10R2 and IL-22R1 expression. c Representative figures of IL-10R2 and IL-22R1 expression in CD45+ cells from the blood. d Abundance of IL-10R2+ and IL-22R1+ in CD45+ cells in the blood. Means and SDs of each mouse at days 0, 3 and 7 were shown. *p < 0.05, ***p < 0.001 by students’ t-test. e Representative figures of IL-10R2 and IL-22R1 expression in CD45+ cells infiltrating the pancreatic tumour (days 3 and 7) or CD45+ cells in the pancreatic tissue (day 0). f Abundance of IL-10R2+CD45+ and IL-22R1+CD45+ cells in tumour tissue. g Strategy for the immunosuppression assay for IL-10R2, IL-22R1-expressing myeloid cells. IL-10R2+/−IL-22R1+/− myeloid cells were sorted from spleens that were harvested from 4 C57BL/6 mice 3 days after orthotropic injection of Pan02. Each subset was cocultured with CFSE-labelled T cells, followed by measuring proliferation and cytotoxicity of CD8+ T cells by flow cytometry. h T cell proliferation (CFSElo, left) and cytotoxicity (Granzyme B [GzB]+, right). Means and SDs of quadruplicate culture were presented. *p < 0.05, **p < 0.01 by students’ t-test.
Fig. 4
Fig. 4. Clinical significance of IL-10R2+ population in PDAC PBMCs for early detection and recurrence after pancreatectomy.
a Receiver operating characteristic (ROC) curve for IL-10R2, IL-22R1, IL-22, combination of IL-22+IL-22R1+IL-10R2 and CA19-9 in PBMCs from PDAC patients (n = 180) vs. controls (CTL, n = 98). Multivariable logistic regression was used to determine the independent predictors of PDAC: variables showing p-values < 0.05 by univariable logistic regression were entered. A combination of IL-10R2, IL-22R1 and IL-22 for PDAC was compared using the DeLong method. b Schematic illustration of the study flow and sample size. c Levels of IL-10R2+, IL-22+ and IL-17+ cells in PBMC from the pre- and postoperative (1 month) samples (paired t-test). d ∆Ct values of IL-10R2, IFNLR1, GPC1 and IL-22 were measured by qPCR and compared between pre-and postoperative (1 month) samples (paired t-test). e A fraction of biomarkers (IL-10R2 or CA19-9) detected among 12 radiologically confirmed recurrence cases in a time-dependent manner (red: over the cut-off value; green: under the cut-off value). f Comparison of the median number of days until tumour recurrence detection after surgery for each biomarker (Mann-Whitney U test).
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