Immune-Related Gene Expression Profiling After PD-1 Blockade in Non–Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma

Abstract

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. .

Baseline neutrophilia, derived neutrophil‐to‐lymphocyte ratio (dNLR), platelet‐to‐lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel

“…However, the use of this biomarker for patient selection poses different biological and technical issues (Kerr et al, ; Patel & Kurzrock, ) and has produced contrasting results in clinical trials, with a significant proportion of patients responding to these agents even in absence of PD‐L1 expression (Borghaei et al, ; Brahmer et al, ; Rittmeyer et al, ). Several different predictive biomarkers beyond PD‐L1 IHC expression have been studied (Chen et al, ; Daud et al, ; Prat et al, ; Rizvi et al, ), but to date none has entered into clinics. Moreover, in some instances the clinical implementation of these methodologies is difficult due to high costs and high level of expertise required.…”

New insights into the role of EMT in tumor immune escape

“…Nevertheless, PD-L1 alone might not be sufficient as a predictive marker of response to anti-PDL1 monoclonal antibodies (Topalian et al, 2016). Promising markers of response are currently under evaluation including the mutational load (Hugo et al, 2016;McGranahan et al, 2016;Rizvi et al, 2015;Rosenberg et al, 2016;Snyder et al, 2014); the MSI , somatic copy number alterations (Davoli et al, 2017), or immune-related signatures (Prat et al, 2017). The presence of tumor-resident CD103 + TILs could also represent a good candidate marker of response to immunotherapy as this TIL population seems to express PD-1 (Djenidi et al, 2015;Komdeur et al, 2016).…”

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

“…Secondly, the immune gene signatures identified in these studies as being associated with anti-PD-1 or PD-L1 therapy response or survival are part of the genes previously identified as the immunological constant of rejection (ICR)-related genes, such as CXCR3, CCR5 ligand genes and IFN-gamma signaling genes. As the authors emphasized, these ICR-related genes are also associated with increased survival across cancer types and responsiveness to other cancer immunotherapy approaches, including anti-CTLA4, adoptive therapy/IL2 and vaccination (8). Thirdly, the findings also suggest that any combination therapy that can increase infiltration of CD4 and CD8 T cells and/or NK cells in tumor microenvironment may enhance the efficacy of immune checkpoint blockage therapy.…”