Immunotherapy is increasingly recognized as an important therapeutic strategy for many cancers. High levels of intratumoral T-cells strongly and consistently correlate with patient survival in multiple cancer types, including high grade serous ovarian cancer (HGSC)2. However, while immune checkpoint blockade antibodies, such as aPD-1 or aCTLA-4, have shown remarkable efficacy in selected cancer types, limited therapeutic benefit has been observed with other types of cancers. Indeed, a recent clinical trial with aPD-L1 showed limited benefit for ovarian cancer patients, with only 1 out of 17 patients having a partial response5. This difficulty of inducing an effective anti-tumor immune response largely stems from the highly immunosuppressive microenvironment present in these tumors. This hostile microenvironment significantly inhibits both the penetration and the function of cytotoxic T lymphocytes (CTLs).
To address this problem, we performed a systems-based approach to identify genes that are highly expressed in cancer associated fibroblasts (CAFs) in tumors with low CTL infiltration. We focus our effort on CAFs due to their well-known immunosuppressive activity as well as their emerging role as a major barrier for CTLs at the tumor site. Through integrative analyses of two independent cohorts of HGSC tumors, we have successfully identified presenilin 1 (PSEN1) as a critical regulator of T-cell trafficking in the tumor microenvironment. Our preliminary data suggest that PSEN1 silencing in ovarian tumors results in a significant increase in CTLs in preclinical models of HGSC. Silencing PSEN1 in CAFs also results in enhanced T-cell activity. On the basis of these compelling preliminary data, we hypothesize that PSEN1 siRNAs delivered using chitosan nanoparticles can overcome the immune privilege and synergistically impact the therapeutic efficacy of existing immune modulating agents in HGSC tumors, leading to induction of a potent tumor-antigen specific immune responses. The overall goal of this study is to develop effective nano-medicine strategies to target PSEN1 in CAFs to enhance the infiltration and function of CTLs in HGSC tumors.