Clinical OMICs - Volume 3, Issue 9 - 10

(continued from previous page) role in immune suppression. PD-1 is expressed in most tumor-infiltrating T cells, including antigen-specific CD8+ T cells. Moreover, PD-1 expression occurs after T-cell activation and has been used as a marker of T-cell exhaustion. The PD-1 receptor has the capacity to bind two ligands, PD-L1 and PD-L2. Typically, when PD-1 is bound to its ligands the result is the elimination of activated effector T-cells once they have completed their tasks-thus making PD-1 an immune checkpoint molecule. When the interaction of PD-1 and PD-L1 is disrupted, for instance with checkpoint inhibitor antibodies such as nivolumab (Opdivo), T cells remain activated, seeking out cancer cells to eliminate. PD-L1 expression has been detected in a number of tumor types, including melanoma, non-small cell lung cancer (NSCLC) renal, and ovarian cancers-underscoring the importance of checkpoint inhibitor drugs. Because of its role in immune suppression and expression pattern in cancerous tissues, PD-L1 has begun to emerge as a potential prognostic marker. Reporting in the April issue of Oncotarget, Chowdhury et al., studied the effectiveness of using PD-L1 as a predictive biomarker for papillary thyroid carcinoma (PTC) and its variants. Using standard immunohistochemical (IHC) staining techniques, the researchers analyzed "251 archived formalin fixed and paraffin embedded (FFPE) surgical tissue samples (66 benign thyroid nodules and 185 10 Clinical OMICs September 2016 PTCs)." The investigators found that "PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease-free survival supporting its potential application as a prognostic marker for PTC." Increased validation of novel biomarkers that provide insight into whether immunotherapies will be successful for individual patients, especially when the timing of treatment is a factor, as it most often is for cancer, is essential. Scheel et al., reporting ahead of print in August for Pathologe, found similar results with the use of IHC methods when surveying for PD-L1 biomarker expression in NSCLC tissue. "The use of PD-L1 IHC in NSCLC is suitable for identification of patients with an increased probability of a clinical benefit from immunotherapy," the authors wrote. "The various proportional cut-offs used to interpret the staining results can be summarized in a total score, which can be reproducibly assessed. The staining patterns of the four assays investigated were, however, not congruent in all situations." Different Direction, Similar Endpoint The PD-1/PD-L1 molecules aren't the only high-profile protein biomarkers associated with immunotherapy. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a receptor that also functions as an immune checkpoint, downregulating immune responses. CTLA-4 is constitutively expressed in regulatory T cells (Tregs) after their activation, serving as an off switch when bound to its ligands CD80 or CD86 present on the surface of antigen-presenting cells (APC). CTLA-4 transmits an inhibitory signal to Tregs, causing them to deactivate-the disruption of which is the basis for the development of antagonist drugs such as ipilimumab (Yervoy). Conversely, researchers have developed CTLA-4 agonist drugs such as abatacept (Orencia) as potential therapies for autoimmune disorders. Previous work done to track the expression patterns of CTLA-4 have shown that the receptor is constitutively expressed in a variety of cancers-in particular, melanoma, for which ipilimumab has been FDA approved for treatment of the disease. Due to the remarkable success of treating melanoma patients with checkpoint inhibitors that target the CTLA-4 pathway, investigators are now attempting to validate CTLA-4 as a prognostic marker for other tumor types. Reporting recently in the Journal of Thoracic Oncology, Deng et al., looked at the roles of CTLA-4 and PDCD1 (gene responsible for PD-1 production) expression in lung cancer patient samples. "We used a lung cancer database of 1715 patients measured by Affymetrix microarrays to analyze the association of gene www.clinicalomics.com http://www.clinicalomics.com

Table of Contents for the Digital Edition of Clinical OMICs - Volume 3, Issue 9