Related Experiment Video
Updated: Jul 29, 2025
Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and
Yujiro Naito1,2,3, Shohei Koyama1,2,4, Kentaro Masuhiro1,3
1Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Abstract:
Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.
Insights
Semaphorin 4A (Sema4A) expression in non-small cell lung cancer (NSCLC) predicts better response to anti-programmed cell death 1 (PD-1) therapy. Sema4A enhances T cell activity, suggesting its potential as a biomarker and therapeutic target for improving cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet limited response rates persist.
- Semaphorin 4A (Sema4A) is known to modulate immune responses in mice, but its function in human tumor microenvironments is not well understood.
Purpose of the Study:
- To investigate the role of human Semaphorin 4A (Sema4A) in non-small cell lung cancer (NSCLC) and its impact on anti-programmed cell death 1 (PD-1) therapy efficacy.
Main Methods:
- Histological analysis of Sema4A expression in NSCLC tissues.
- Assessment of the correlation between Sema4A expression and response to anti-PD-1 antibodies.
- Investigation of Sema4A's effects on CD8+ T cell activation, proliferation, and exhaustion in murine models and patient-derived T cells.
- Analysis of downstream signaling pathways, including mTORC1 and polyamine synthesis.
Main Results:
- Sema4A-positive NSCLC showed significantly better response to anti-PD-1 therapy compared to Sema4A-negative tumors.
- SEMA4A expression in human NSCLC was primarily from tumor cells and correlated with T cell activation.
- Sema4A enhanced CD8+ T cell cytotoxicity and proliferation while preventing terminal exhaustion by upregulating mTORC1 and polyamine synthesis.
- Recombinant Sema4A improved T cell activation in isolated tumor-infiltrating T cells from cancer patients.
Conclusions:
- Sema4A is a potential predictive biomarker for anti-PD-1 therapy response in NSCLC.
- Sema4A promotes anti-tumor immunity by enhancing T cell function.
- Targeting Sema4A could be a novel strategy to improve the efficacy of cancer immunotherapy.
