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Tumor Stroma Infiltrating T Cells Predict the Efficacy of Anti-CTLA-4 Antibody in NSCLC
Hiroshi Saijo1,2, Yoshihiko Hirohashi2, Toshiyuki Sumi3
1Department of Respiratory Medicine, Sapporo Minami-Sanjo Hospital, Sapporo, Japan; h_saijo@h-keiaikai.or.jp.
Background/Aim:
Although various therapeutic options are available for advanced or recurrent non-small cell lung cancer (NSCLC), the optimal criteria for selecting combination therapies involving anti-programmed death-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) antibodies with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies remain unclear. Clinical trials suggest potential benefits of the treatment with anti-CTLA-4 antibodies in NSCLC with PD-L1 <1%; however, concerns persist regarding the increased risk of immune-related adverse events (irAEs). Therefore, identifying reliable biomarkers to guide the use of anti-CTLA-4 antibodies is crucial.
Patients And Methods:
We performed immunohistochemical staining to assess intratumoral tumor-infiltrating lymphocytes (iTILs) and stromal tumor-infiltrating lymphocytes (sTILs) expressing CD8 or FOXP3 using surgically obtained specimens. The association between these cells and the clinical efficacy of the treatment with nivolumab plus ipilimumab was evaluated using univariate and multivariate analyses in NSCLC patients with PD-L1 <1%. Kaplan-Meier analysis was conducted to assess survival outcomes.
Results:
Univariate analysis revealed a significant correlation between progression-free survival and sTIL infiltration, but not iTIL infiltration. Patients who responded to therapy exhibited significantly higher CD8+ and lower FOXP3+ iTIL infiltration, as reported previously. Notably, responders also demonstrated significantly higher infiltration of both CD8+ and FOXP3+ sTILs. Moreover, high stromal infiltration of CD8+ T cells was significantly associated with prolonged overall survival, while high FOXP3+ sTILs infiltration showed a trend toward improved overall survival.
Conclusion:
Despite the increased risk of irAEs, patients with high stromal infiltration of CD8+ and FOXP3+ T cells may derive meaningful clinical benefit from anti-CTLA-4 antibody therapy. Assessing these immune parameters could aid in appropriate patient selection and contribute to optimizing therapeutic outcomes.
Insights
High stromal infiltration of CD8+ and FOXP3+ T cells may predict benefit from anti-CTLA-4 antibody therapy in non-small cell lung cancer (NSCLC) patients with low PD-L1 expression, despite risks of immune-related adverse events.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Optimal selection criteria for combination therapies involving anti-PD-1/PD-L1 and anti-CTLA-4 antibodies in advanced/recurrent NSCLC are unclear.
- While anti-CTLA-4 therapy shows potential in PD-L1 <1% NSCLC, increased immune-related adverse events (irAEs) are a concern.
- Biomarkers are needed to guide the use of anti-CTLA-4 antibodies in NSCLC.
Purpose of the Study:
- To investigate the role of intratumoral (iTILs) and stromal (sTILs) tumor-infiltrating lymphocytes (CD8+, FOXP3+) as biomarkers for anti-CTLA-4 therapy efficacy in NSCLC.
- To evaluate the association between TIL infiltration and clinical outcomes in NSCLC patients with PD-L1 <1% treated with nivolumab plus ipilimumab.
Main Methods:
- Immunohistochemical staining for CD8+ and FOXP3+ iTILs and sTILs in NSCLC specimens.
- Univariate, multivariate, and Kaplan-Meier analyses to assess the correlation between TILs and clinical efficacy (progression-free survival, overall survival).
- Evaluation in NSCLC patients with PD-L1 <1% receiving nivolumab plus ipilimumab.
Main Results:
- High sTIL infiltration correlated significantly with progression-free survival.
- Responders showed higher CD8+ and lower FOXP3+ iTILs, and higher CD8+ and FOXP3+ sTILs.
- High CD8+ sTILs significantly predicted prolonged overall survival; high FOXP3+ sTILs showed a trend toward improved overall survival.
Conclusions:
- Patients with high stromal infiltration of CD8+ and FOXP3+ T cells may benefit from anti-CTLA-4 antibody therapy.
- Assessing these stromal immune parameters can aid in patient selection for anti-CTLA-4 therapy.
- This approach may help optimize therapeutic outcomes in NSCLC, despite irAE risks.
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