Method of determining risk for skin cancer development and skin cancer therapeutic prevention by measuring PD-1/PD-L1 signaling pathway members

Inventors

Curiel, Clara N. • Baker, Amanda Fern • Dickinson, Sally E. • Petricoin, III, Emanuel F.

Assignees

George Mason University • University of Arizona

Abstract

The present invention relates to a method of using family and/or regulatory members of the PD-1/PD-L1 pathway as predictive markers for risk of skin cancer development and as targets for therapeutic prevention of pre-malignant (or pre-cancerous) skin lesions and non-melanoma skin cancer (NMSC). This invention will allow for quantitative measurements of UV-induced expression of PD-1/PD-Li signaling pathway family members (e.g., PD-1, PD-L1, PD-L2) and/or PD-1/PD-L1 regulatory factors including AP-1 and NFκB family members in skin tissue of individuals to determine an individual's 1) risk for skin cancer development and 2) appropriate prophylactic treatment strategy to prevent skin cancer development. This information will facilitate identification of those patients at risk for pre-malignant (or pre-cancerous) skin lesions or subsequent NMSC lesions who would benefit from a PD-1/PD-L1 pathway suppressing therapy to prevent skin cancer development.

Core Innovation

The invention describes a method comprising irradiating a portion of skin, obtaining an irradiated skin sample portion, and detecting expression of programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) in the irradiated skin sample portion and in a non-irradiated skin sample. It applies the detected PD-1/PD-L1 expression as a quantitatively measurable UV-induced response in skin, including an acute solar-simulated light context.

The approach further measures differential expression, including increased PD-L1 after acute solar-simulated light in human skin and HaCaT cells, and characterizes expression in terms of protein expression and gene expression (mRNA). It includes analysis of regulatory factors associated with the PD-1/PD-L1 pathway, including AP-1 and NF-κB, in samples obtained from a region of interest before versus after irradiation.

The invention uses the differential expression of PD-1/PD-L1 pathway members as a predictive marker of risk for skin cancer development, including cutaneous squamous cell carcinoma (cSCC) and non-melanoma skin cancer (NMSC). It also contemplates using the risk assessment for longitudinal patient stratification and for guiding prophylactic or therapeutic prevention strategies that include PD-1/PD-L1 pathway inhibitors.

Claims Coverage

The independent claim covers a method that irradiates skin and detects PD-1 or PD-L1 expression in irradiated and non-irradiated skin sample portions, enabling UV-induced differential readouts. The main inventive features in the dependent claims refine the irradiation dose range and broaden the PD-1/PD-L1 detection modalities to multiple expression and activity forms.

Across the independent and dependent claims, the inventive coverage centers on irradiating skin and comparing irradiated versus non-irradiated samples to detect PD-1 or PD-L1 expression, with refinements to a specific MED dose range and to PD-1/PD-L1 measurement across protein expression, gene expression, gene copy number, and/or activity.

Stated Advantages

Documented Applications