Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients

Abstract

Objectives A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8 + T cell infiltration, HLA class-I and PD-L1 expression in the tumor. Materials and methods Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8 + T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan-Meier methodology. Results 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8 + T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8 + T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007). Conclusion This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8 + T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.

Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma

“… 4 17 Cytotoxic T cell activity towards cancer cells in the TME is suggested to be an independent factor of the PD-L1 tumor proportion score and tumor mutation burden. 2 18 …”

“… 1 Similarly, other biomarkers, such as CD8 + T cell infiltration and tumor mutational burden, individually or combined, have been considered as biomarkers. 2 3 Interestingly, recent evidence suggests that transforming growth factor beta (TGF-β), cancer-associated fibroblasts (CAFs) and immune-exclusion in tumor tissue are associated with worse clinical outcome after PD-L1 or PD-1 inhibition in solid cancer. 4–6 Those immune-excluded tumors are characterized by a collagen-rich peritumoral stroma (tumor fibrosis) that blocks the interaction between CD8 + T cells and tumor cells.…”

Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer

“…Expression of programmed death-ligand 1 (PD-L1) and tumor mutational burden (TMB) have previously been determined in a subset of patients of cohort 1 (n=26; patients with stage IV NSCLC) using archival formalinfixed, paraffin-embedded tissue samples. 28 Baseline expression of PD-L1 has been determined using antibody clone SP263 (Roche Diagnostics, Tucson, Arizona, USA), whereas TMB has been measured using the Oncomine TML assay (Thermofisher Scientific, Waltham, Massachusetts, USA).…”

Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer

“…The molecular profile like TMB (tumor mutation burden), driver mutations in EGFR, KRAS, BRAF, ALK could impact the efficacy of immunotherapy in NSCLC patients. 33 34 Lastly, no tumor-specific antigens from the target cells were used during T cell priming, so the measured cytotoxic effects were not tumor-specific. Nevertheless, a functional CD3 antibody was applied to activate T cells more specifically.…”