Most cancer patients fail to respond to immune checkpoint inhibitors, hence biomarkers needed in order to predict clinical benefit in individual patients. The goal of this study was to augment the prediction accuracy by identifying and testing novel candidate biomarkers that could envisage response in patients with metastatic melanoma. The analysis had two specific features: validation against previously published predicting biomarkers and characterization of patients’ transcriptomes at individual gene and pathway levels, where network enrichment analysis (NEA) integrated disparate genes into pathway scores. First, candidate transcription-based biomarkers were discovered in our cohorts via correlation to clinical benefit and then analyzed for significance by covariate adjustment. Secondly, the candidates performance was validated using a similar previously published NanoString-based gene dataset. In the anti-PD1 cohort, we identified genes which were informative on the clinical benefit regardless of the known determinants. In the anti-CTLA4 cohort, the individual gene analysis did not yield any significant and validated associations. However instead, we revealed a number of NEA-based correlates between disease progression and relevant pathways as well as a number of immune-related differentially expressed gene lists.
Torbjörn Ramqvist, Anders Näsman, Bo Franzén, Cinzia Bersani, Andrey Alexeyenko, Susanne Becker, Linnea Haeggblom, Aeneas Kolev, Tina Dalianis, Eva Munck-Wikland
Human papillomavirus (HPV) is a major etiological factor for tonsillar and the base of tongue cancer. HPV-positive and HPV-negative samples were analyzed for expression of 167 proteins using two Olink assays. Major differences in protein expression between cancer and normal tissue were identified, especially in chemo- and cytokines. A number of immunoregulatory proteins and chemokines were differently expressed in HPV-positive vs HPV-negative cancers. Several proteins were potentially related to clinical outcome for HPV-positive or HPV-negative tumors. For HPV-positive tumors, these were mostly related to angiogenesis and hypoxia. Differences in immune related proteins between HPV-positive and HPV-negative samples reflected the stronger activity of the immune defense in the former. Angiogenesis related proteins might serve as potential targets for therapy of HPV-positive cases.
Bo Franzén, Andrey Alexeyenko, Masood Kamali‐Moghaddam, Thomas Hatschek, […] Giuseppe Masucci, Gert Auer, Ulf Landegren, Rolf Lewensohn
There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and to follow-up personalized cancer therapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissues; however, the minute sample amounts require sensitive multiplex molecular analysis to achieve clinical utility. We have applied proximity extension assays and NanoString technology for analyses of proteins and of RNA, respectively, in FNA samples. Using samples from patients with breast cancer (BC, n = 25) or benign lesions (n = 33), we demonstrate that these FNA-based molecular analyses (a) can offer high sensitivity and reproducibility, (b) may provide correct diagnosis in shorter time and at a lower cost than current practice, (c) correlate with results from routine analysis (i.e., benchmarking against immunohistochemistry tests for ER, PR, HER2, and Ki67), (d) could be divided into two main clusters, characterized by differences in expression levels of the estrogen receptor (ER) and the proliferation marker Ki67, and (e) may also help identify new markers related to immunotherapy. A specific 11-protein signature, including FGF binding protein 1, decorin, and furin, distinguished all cancer patient samples from all benign lesions in our main cohort and in smaller replication cohort. We also identified three signatures that could predict Ki67status, ER status, and tumor grade, respectively, based on a small subset of proteins dominated by chemokines. Expression profiles of CCL13 in benign lesions and BC have never previously been found to correlate with proliferation (P = 0.00095), suggesting a role in advanced BC. Due to the minimally traumatic sampling and clinically important molecular information for therapeutic decisions, this methodology is promising for future immunoscoring and monitoring of treatment efficacy in BC.