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Updated: Jun 4, 2026
09:32
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Single-Cell Analysis Identifies LYPD6B as a Tumor-Intrinsic Candidate Associated With Immunotherapy Nonresponse in
Yifei Wang1,2,3, Haiwei Quan2,4, Zhiguang Xu2
1Center for Cancer Immunotherapy of Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
Thoracic Cancer
|June 3, 2026
Summary
Immune checkpoint blockade (ICB) resistance in breast cancer is linked to the gene LYPD6B. Targeting LYPD6B may improve responses to PD-(L)1 therapies by overcoming tumor-intrinsic immune evasion.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint blockade (ICB) offers durable responses in some breast cancer patients, but many do not benefit from anti-PD-1/PD-L1 therapy.
- Tumor microenvironment (TME) and tumor-intrinsic immune evasion mechanisms in responders (R) versus nonresponders (NR) are critical for improving ICB efficacy.
Purpose of the Study:
- To investigate the differences in TME and tumor-intrinsic factors between R and NR breast cancer patients treated with PD-(L)1 therapy.
- To identify novel therapeutic targets for overcoming resistance to ICB in breast cancer.
Main Methods:
- Integrated three public single-cell RNA sequencing (scRNA-seq) datasets from PD-(L)1-treated breast cancer patients (51 patients, 327022 cells).
- Analyzed paired pre- and post-treatment samples to understand treatment effects.
- Performed pseudotime analysis on T cells, tumor-intrinsic screening, functional assays, drug-repurposing analysis, immunohistochemistry (IHC), and pan-cancer analyses.
Main Results:
- Responders (R) showed increased CD8+ T cell infiltration, enhanced interferon-response activity, and myeloid/B-cell remodeling compared to nonresponders (NR).
- T cells in R exhibited patterns of activation, cytotoxic differentiation, and exhaustion, indicative of effective ICB response.
- Identified LYPD6B, a membrane gene upregulated in NR cancer cells, which suppresses antigen processing/presentation and IFNα/β signaling.
- LYPD6B ablation impaired cancer cell proliferation and clonogenic growth, inducing apoptosis.
- Venetoclax was found to bind LYPD6B and replicate its antiproliferative effects.
- LYPD6B was confirmed to localize to tumor cells and associate with immune infiltration and checkpoint expression.
Conclusions:
- LYPD6B is a tumor-intrinsic mediator of immune evasion and PD-(L)1 resistance in breast cancer.
- Targeting LYPD6B presents a promising strategy for combination immunotherapy to improve outcomes in breast cancer patients resistant to current therapies.
