Description and purpose
Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of metastatic renal cell carcinoma (mRCC) and non-small-cell lung cancer (NSCLC) in first- and more-line settings. However, only a limited fraction of patients will achieve a long-term benefit from ICIs, underlining the urgent need to identify prognostic and predictive biomarkers. A major issue to optimize cancer immunotherapy, guiding patient selection, is to decipher the multifaceted events implicated in the response to ICIs. Several tissue, circulating and molecular factors, reflecting the immune-inflammatory status of mRCC and NSCLC patients, have been proposed as potential determinants of ICI response, although with controversial results. In this constantly evolving context, the dualrole played by cholesterol in cancer growth and immune response, and specifically, its cellular efflux mediated by ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), is endorsing in-depth investigations on the impact of cholesterol metabolism on tumor immune microenvironment (TIME), immune cell function and ICI efficacy.
On this basis, we hypothesized that by exploring the relationship between cholesterol homeostasis and immune cells at both tumor tissue and peripheral blood levels, we might provide new prognostic and predictive tools in ICI-treated mRCC and NSCLC patients.
The project will involve two distinct prospective cohorts of patients affected by mRCC and NSCLC undergoing ICI-based regimens (mRCC: ICIs + Tyrosine kinase inhibitors [TKIs] or ICI + ICI; NSCLC: ICIs + platinum-based chemotherapy or single-agent ICIs). Two main research topics will be investigated:
- Patient specific immune profile: a) on tissue samples: immunohistochemical (IHC) characterization of TIME, including Tumor Infiltrating Lymphocytes (TILs) subpopulations and PD-L1 status; b) on peripheral blood samples: flow-cytometric analysis of circulating immune phenotypes; serum levels of sPD-L1 and CD163L1; cytokine/chemokine milieu.
- Cholesterol homeostasis: a) on tissue samples: IHC expression of ABCA1/G1 cholesterol transporters, LXR-α and LRP-1; b) on peripheral blood samples: cholesterolemia; ABCA1/G1-mediated Cholesterol Efflux Capacity (CEC), ApoA1/ApoE concentrations.
Cholesterol efflux-centred parameters will be subsequently correlated with patient outcome and immune-inflammatory features. By this comprehensive immune-metabolic approach we expect to offer new valuable insights into the complex interplay between
cholesterol homeostasis, anti-cancer immune response and ICI effectiveness in mRCC and NSCLC patients undergoing first-line ICI-based regimens.
Purpose
LINCHOLM study aims to provide a comprehensive immune-metabolic characterization of patients with advanced RCC or NSCLC receiving first-line treatment in order to:
- Objective 1: Determine whether tissue and circulating levels of master regulators of cholesterol homeostasis impact on mRCC and NSCLC progression-free survival (PFS) [primary endpoint]
- Objective 2: Determine whether tissue and circulating levels of master regulators of cholesterol homeostasis impact on mRCC and NSCLC overall survival (OS) and response to ICIs (objective response rate, ORR) [secondary endpoints]
- Objective 3: Assess whether tissue and circulating levels of master regulators of cholesterol homeostasis correlate with immune-microenvironmental features
Exploratory objective 4. Explore potential correlations between tissue and blood compartments in terms of both cholesterol-related mediators and bio-immune parameters
Expected results
The findings of the present project can narrow the gap in our understanding of biological and immunological events implicated in cancer development and response to treatment, thus significantly improving patient management. The possibility to exploit different sources of information, easily available as per-clinical practice, such as tissue specimens and peripheral blood samples, may allow us to faithfully portray the tumor-host interactions, specifically focused on patient cholesterol metabolism and immune response. In addition, the study would enable HDL functionality (CEC) in cancer development to be characterised for the first time, linking inflammation to cholesterol metabolism.
Achieved results
As of today, approximately 90% of the expected patients have been enrolled and both the blood and tissue analyses are underway.
