Engineered milk exosomes for lung cancer immunotherapy – PI: Farrukh Aqil

Immunotherapy has been gaining increased attention in cancer treatment. Considering the versatile mechanisms of tumor evasion from the host immune system, the RNAi approach can be utilized targeting different molecules to enhance the immune response against tumors. In most cancer cells PD-L1 binds to PD1 on the surface of lymphocytes and allows the immune system to escape. The interaction between PD-L1 and PD-1 on CD8+ T cells results in upregulation of Cbl E3 ubiquitin ligases in activated T cells and subsequent downmodulation of T cell receptors. shRNA-mediated PD-L1 silencing leads to hyperactivated proinflammatory T cell receptor CD8+ T cells with considerably accelerated anti-tumor immune responses. The knockdown of PD-L1/PD-L2 improves T-cell proliferation and cytokine production. Anti PD-1/PD-L1- based therapeutics (atezolizumab, avelumab and durvalumab) have significantly improved the survival of lung cancer patients. Yet, the overall response rate remains unsatisfactory (<20%) owing to the fact that cancer cells release PD-L1 in soluble form into the tumor microenvironment, interfering with antibody treatment efficacy. With siRNA therapy, reduced PD-L1 production on the cancer cell surface allows T-cells to detect cancer cells more efficiently and prevent tumor progression.

Thus, the limitations of cancer immunotherapy to solid tumors due to issues such as immunosuppressive tumor microenvironment, ineffective trafficking, tumor antigen heterogeneity and other severe adverse effects can be addressed and overcome using siRNA therapy. 

The goal of this project is to use novel nanoplatform of exosome-polyethyleneimine (PEI) matrix (EPM) to deliver siRNA. I hypothesize that siPD-L1 embedded in EPM is protected from nuclease degradation and functions to knockdown tumor surface bound PD-L1 leading to lung cancer cells inhibition. The strategy will be tested against lung cancer as a model with wide applications. The formulation will be functionalized with folic acid (FA) to target tumor cells which have higher expression of folate receptors.