Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational
Libin Zhang1, Yanhui Chen2, Han Wang1
1Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.
Background:
Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-small cell lung cancer (NSCLC).
Methods:
Tumor tissue samples of a total of 378 patients from two NSCLC cohorts were collected retrospectively. Tumor genetic variations were measured by targeted next-generation sequencing of 543 oncogenes. Tils were assessed by multiplex immunohistochemistry assay. Correlations among Tils, tumor genetic variations, and clinicopathological characteristics were analyzed.
Results:
The levels of CD8+PD-L1+ Tils varied in NSCLC tumor tissues. Tumor samples with high CD8+PD-L1+ Tils had higher levels of CD8+ Tils, CD68+ macrophages, PD-L1+ tumor cells, PD-1+ Tils, and CD163+ M2-type macrophages, and also had a higher tumor mutation burden, all of which collectively constituted a typically hot but immunosuppressive tumor microenvironment. Therefore, in a non-immunotherapy cohort, we observed that the higher the CD8+PD-L1+ Tils level in the tumor tissue, the worse the prognosis (progression-free survival; cohort A, stage I-II tumor; p=0.005). Contrarily, in an immunotherapy cohort, where the immune suppression was blocked by anti-PD-1 treatment, the higher the CD8+PD-L1+ Tils level, the better the response to the anti-PD-1 treatment (complete response/partial response vs stable disease/progressive disease; cohort B; p=0.0337).
Conclusions:
CD8+PD-L1+ Tils may be an indicator of the hot but immunosuppressive tumor microenvironment which is related to a high tumor mutation burden. PD-1 pathway blockade therapy can help to mitigate this immunosuppression and obtain better curative effects.
Insights
High CD8+PD-L1+ tumor-infiltrating lymphocytes (Tils) indicate a hot but immunosuppressive tumor microenvironment in non-small cell lung cancer (NSCLC). PD-1 pathway blockade therapy effectively mitigates this immunosuppression, improving treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Programmed cell death ligand 1 (PD-L1) on tumor and immune cells influences response to PD-1 pathway blockade therapy.
- The role of CD8+PD-L1+ tumor-infiltrating lymphocytes (Tils) in the non-small cell lung cancer (NSCLC) tumor microenvironment requires examination.
Purpose of the Study:
- To investigate the significance of CD8+PD-L1+ Tils within the NSCLC tumor microenvironment.
- To correlate CD8+PD-L1+ Tils levels with tumor genetics, microenvironment characteristics, and patient prognosis.
Main Methods:
- Retrospective analysis of 378 NSCLC patient tumor samples from two cohorts.
- Targeted next-generation sequencing for tumor genetic variations (543 oncogenes).
- Multiplex immunohistochemistry assay for Tils assessment and correlation analysis.
Main Results:
- High CD8+PD-L1+ Tils correlate with increased CD8+ Tils, macrophages (CD68+, CD163+), PD-L1+ tumor cells, PD-1+ Tils, and higher tumor mutation burden, indicating a hot, immunosuppressive microenvironment.
- In a non-immunotherapy cohort, higher CD8+PD-L1+ Tils levels correlated with worse progression-free survival (p=0.005).
- In an immunotherapy cohort, higher CD8+PD-L1+ Tils levels correlated with better response to anti-PD-1 treatment (p=0.0337).
Conclusions:
- CD8+PD-L1+ Tils may signify a hot, immunosuppressive tumor microenvironment associated with high tumor mutation burden.
- PD-1 pathway blockade therapy can overcome this immunosuppression, leading to improved therapeutic effects in NSCLC.
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