Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy

Abstract

Background No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non–small-cell lung cancer (NSCLC). Methods We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas ( n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types. Results In prognostic cohorts, high CD8A expression was associated with longer OS ( p = 0.02), while high CD274 mRNA was associated with poor prognosis ( p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) ( p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS ( p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures. Conclusion CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.

Immunotherapy in Non–Small Cell Lung Cancer: Facts and Hopes

“…In multiple tumor types, the presence of prominent T-cell infiltration and IFNg-related mRNA signatures (indicative of increased adaptive antitumor responses) at baseline have been consistently associated with increased sensitivity to ICIs and improved prognosis (7,(49)(50)(51)(52). In patients with advanced NSCLC, detection of increased CD8 þ tumor-infiltrating lymphocytes (TIL) by IHC or CD8A mRNA transcripts in baseline tumor specimens is associated with significantly longer PFS after treatment with PD-(L)1 inhibitors; this association was strengthened when combined with PD-L1 at the protein and mRNA level, suggesting that integration of these biomarkers may provide increased predictive value (53). Another study using multiplexed quantitative immunofluorescence to measure TILs in formalin-fixed, paraffin-embedded (FFPE) tumor specimens identified a significant association among baseline CD3 þ levels, durable clinical benefit and OS in NSCLC patients treated with ICIs (41).…”

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

“…Clinical studies evaluating the efficacy of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have proposed different potential markers such as tumorintrinsic immune checkpoint expression, the intensity of intratumoral CD8 + T cell infiltrates, or an enhanced interferon-γ signature to be predictive for therapy response. [31][32][33][34][35] Currently, immunohistochemically determined receptor status is the only widely used biomarker Open access prior immune checkpoint inhibition. However, the use of PD-L1 IHC as a predictive biomarker is confounded by multiple difficulties, such as the usage of different antibodies and expression scores, as well as interlaboratory and interobserver variability.…”

Low CD8⁺ T Cell Infiltration and High PD-L1 Expression Are Associated with CD44⁺/CD133⁺ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer

“…infiltrating lymphocytes (TILs) had the best survival, and the patients with PD-L1 + and CD8 low TILs had the worst survival [40]. NSCLC patients with low CD8 expression and high PD-L1 expression had very poor outcomes, with a median OS of 3.7 months, while the median for all other patients was 8 months [48]. In human medulloblastoma, patients with high expression of PD-L1 and low infiltration of CD8 + lymphocytes had a significantly worse outcome, with a 5-year survival rate of 15%, as compared with the other patients, who had a 5-year survival rate of nearly 90% [38].…”

“…expression has been proposed [37] and this concept has been applied to predict prognosis in patients with medulloblastoma [38], lung [39], and gallbladder cancer [40] by using immunostaining. We therefore performed IHC staining to study whether this phenomenon can be found in PC.…”