Dataset Information

Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas.

ABSTRACT:

Background

Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has emerged as a novel immunotherapy candidate, which deserves a comprehensive investigation in lung adenocarcinoma (LUAD).

Methods

Multiplex fluorescence-based immunohistochemistry was conducted to assess Siglec-15 expression and tumor-infiltrating immune cells in LUAD from Tianjin cohort, with validation cohorts Xinchao 04 and 07.

Results

This study revealed that Siglec-15 was positively correlated with CD8⁺ T cells and tumor-associated macrophages (TAMs) infiltration, but CD8⁺ T cells were mostly infiltrated in the stroma area, not in the tumor area. Spatially, fewer CD8⁺ T cells surrounded Siglec-15⁺ tumor cells in PD-L1^- cells, and more TAMs surrounded Siglec-15⁺ tumor cells in PD-L1^-/+ cells. Siglec-15⁺ TAMs infiltrated with more CD8⁺ T cells, and were closer to CD8⁺ T cells than Siglec-15^- TAMs and Siglec-15⁺ tumor cells. Siglec-15⁺ TAMs infiltrated with more Tregs and were closer to Tregs than Siglec-15⁺ tumor cells. Siglec-15⁺ tumor cells or TAMs reversed CD8⁺ T cells prognosis value, and enhanced the prognosis value of Tregs and TAMs. The immunotyping based on Siglec-15 and CD8A / CD8⁺ T cells revealed that patients with high CD8A and Siglec-15 expression exhibited immune activation. Patients with low CD8A expression / CD8⁺ T cells infiltration and Siglec-15 overexpression were related to the activation of immunosuppressive signature and metabolism-related pathway, and infiltrated with more TAMs.

Conclusions

We revealed the distinct characteristics between Siglec-15⁺ tumor cells and TAMs in relation to CD8⁺ T cells, and a unique relationship between Siglec-15 and immunosuppressive TIME in LUAD, which may provide potential value for anti-Siglec-15 therapy.

SUBMITTER: Li B

PROVIDER: S-EPMC10483852 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas.

Li Baihui B Guo Yan Y Yi Yeran Y Huang Ziqi Z Ren Yulin Y Wang Hao H Yang Lili L

Journal of translational medicine 20230906 1

<h4>Background</h4>Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has emerged as a novel immunotherapy candidate, which deserves a comprehensive investigation in lung adenocarcinoma (LUAD).<h4>Methods</h4>Multiplex fluorescence-based immunohistochemistry was conducted to assess Siglec-15 expression and tumor-infiltrating immune cells in LUAD from Tianjin cohort, with validation cohorts Xinchao 04 and 07.<h4>Results</h4>This study revealed that Siglec-15 was positively correlated w ...[more]

PMID: 37674198

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Project description:ImportanceIntratumoral heterogeneity has been recognized as a significant barrier in successfully developing targetable biomarkers for gastroesophageal adenocarcinoma (GEA) and may affect neoadjuvant precision medicine approaches.ObjectiveTo describe intratumoral spatial heterogeneity of tumor cell populations in nonmetastatic GEA and its association with survival.Design, setting, and participantsThis case series retrospectively identified 41 patients with GEA who underwent up-front surgical resection at a tertiary referral cancer center from January 1, 1989, through December 31, 2013. Survival was calculated from date of surgery to date of death through June 1, 2017. Data were analyzed from June 2, 2017, to March 1, 2019.Main outcomes and measuresOverall survival, intratumoral clonal composition determined by genomic single-nucleotide variation array and bioinformatic analysis, and intercellular tumoral distances determined by multiprobe fluorescence in situ hybridization.ResultsAmong the 41 patients included in the analysis (22 men [54%]; mean [SD] age, 63 [12] years), a high proportion (19 [46%]) presented with tumors possessing high intratumoral heterogeneity. Kaplan-Meier analysis demonstrated that cases with an intratumoral clonal composition count of at least 2 exhibited worse survival compared with cases with a clonal composition count of 0 to 1 (univariate hazard ratio, 3.92; 95% CI, 1.27-12.08; P = .02). This finding remained significant on multivariate analysis controlling for stage, Lauren histologic subtype, receipt of adjuvant therapy, and age (multivariate hazard ratio, 4.55; 95% CI, 1.09-19.04; P = .04). Multiprobe fluorescence in situ hybridization demonstrated intratumoral clonal populations coexisting at submillimeter distances with differing relevant oncogenic copy number alterations, such as EGFR, JAK2, FGFR2, MET, CCND1, KRAS, MYC, PIK3CA, CD274, and PDCD1LG2.Conclusions and relevanceThis study found that spatial intratumoral heterogeneity of oncogenic copy number alterations exists before metastatic dissemination, and increased heterogeneity was associated with worse outcomes in resected GEA. Baseline heterogeneity illustrates the challenges in GEA targeted therapy. Further study may offer insight into strategies on combinatorial and/or sequential targeted and immunotherapeutic approaches.

Project description:Immunotherapy is less effective in patients with epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). Lower programmed cell death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB) are reported to be the underlying mechanism. Being another important factor to affect the efficacy of immunotherapy, tumor microenvironment (TME) characteristics of this subgroup of NSCLC are not comprehensively understood up to date. Hence, we initiated this study to describe the specific TME of EGFR-mutant lung adenocarcinoma (LUAD) from cellular compositional and functional perspectives to better understand the immune landscape of this most common subtype of NSCLC. We used single-cell transcriptome sequencing and multiplex immunohistochemistry to investigate the immune microenvironment of EGFR-mutant and EGFR wild-type LUADs and determined the efficacy of immunotherapy. We analyzed single cells from nine treatment-naïve samples and compared them to three post-immunotherapy samples previously reported from single cell perspective using bioinformatics methods. We found that EGFR-mutant malignant epithelial cells had similar characteristics to the epithelial cells in non-responders. EGFR-mutant LUAD lacked CD8+ tissue-resident memory (TRM) cells, which could promote tertiary lymphoid structure generation by secreting CXCL13. In addition, other cell types, including tumor-associated macrophages and cancer-associated fibroblasts, which are capable of recruiting, retaining, and expanding CD8+ TRM cells in the TME, were also deficient in EGFR-mutant LUAD. Furthermore, EGFR-mutant LUAD had significantly less crosstalk between T cells and other cell types via programmed cell death-1 (PD-1) and PD-L1 or other immune checkpoints compared with EGFR wild-type LUAD. Our findings provide a comprehensive understanding of the immune landscape of EGFR-mutant LUAD at the single-cell level. Based on the results, many cellular components might have negative impact on the specific TME of EGFR-mutant LUAD through influencing CD8+ TRM. Lack of CD8+ TRM might be a key factor responsible for the suppressive TME of EGFR-mutant LUAD.

Dataset Information

Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas.

Background

Methods

Results

Conclusions

Publications

Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas.

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