PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer

Abstract

PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1+ CD11b+ cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1+ myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null.

Systemic Blood Immune Cell Populations as Biomarkers for the Outcome of Immune Checkpoint Inhibitor Therapies

“…In a clinical case study, two tumor PD-L1-negative NSCLC patients with similar clinical history exhibited a remarkably different response to atezolizumab. The responder patients showed a high baseline percentage of PD-L1-expressing myeloid cells [6]. This observation was corroborated in an exploratory follow-up study of 31 patients with advanced NSCLC, suggesting that quantification of systemic PD-L1 + myeloid cell subsets could complement other biomarkers for patient stratification, independently of PD-L1 expression in tumor biopsies.…”

“…Moreover, many PD-L1 detection protocols are not currently standardized [5]. For example, PD-L1 expression in myeloid cells may also play a role in response or resistance for the treatment of PD-L1 negative tumors, even when anti-PD-L1 antibody (atezolizumab) was the treatment of choice [6]. In these cases, the relative abundance of PD-L1 + CD11b + myeloid cells in systemic blood correlated with clinical responses in lung cancer.…”

Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

“…Tumor survival can depend on the PD-L1/PD-1 pathway to attenuate immunogenicity and facilitate resistance to anti-apoptotic stimuli (Hirano et al, 2005;Azuma et al, 2008;Keir et al, 2008;Gato-Canas et al, 2017;Escors et al, 2018). PD-L1 is overexpressed in many tumor types to evade the immune attack and its expression generally (but not always) correlates with progression (Gato-Canas et al, 2017;Escors et al, 2018;Bocanegra et al, 2019;Kattan et al, 2019). PD-1 is expressed in T lymphocytes and interferes with their activation when bound with their ligands PD-L1, inhibiting the effector phase and thus dampening the ability of these T cells to kill cancer cells (Keir et al, 2008;Gato-Canas et al, 2017;Zuazo et al, 2019).…”

“…Some immunohistochemistry assays to quantify PD-L1 expression are currently FDA-approved such as Dako 28-8, Dako 22C3, Ventana SP142, and Ventana SP263. However, the systems of detection are not currently standardized, as different immunochemistry assay and scoring system offer different classifications for tumor PD-L1 status (Arasanz et al, 2018;Bocanegra et al, 2019). Additionally, PD-L1 expression can be highly variable and heterogeneous.…”

“…Additionally, PD-L1 expression can be highly variable and heterogeneous. Some patients with PD-L1-negative tumors may still benefit from anti-PD-L1/PD-1 therapies as PD-L1 is also expressed by many other cell types including myeloid antigen-presenting cells (Karwacz et al, 2011;Motzer et al, 2015;Horn et al, 2017;Bocanegra et al, 2019). Because of these limitations, PD-L1 expression as a predictive biomarker for responses is still under debate.…”