Lay Abstract
We have recently conducted a prospective study on patients affected by desmoid-type fibromatosis under active surveillance (AS), aiming to understand if changes in tumor immune microenvironment (TIME) and circulating immune populations correlate and influence spontaneous tumor regression. Our analysis suggested dysregulations of immune cells in TIME and peripheral blood in patients experiencing tumor regression. These findings support the hypothesis that the immune system may play a central role in inducing tumor regression. We are collecting additional blood and tumor tissues in a new prospective multicenter study in order to validate our previous findings in a larger patient population.
Our aim is to deeply characterize immune cells present in desmoid tumor tissue through spatial omic approaches to understand their cross-talk with tumor cells in the TIME. Additionally, we hypothesize that in patients who undergo a systemic therapy, changes in TIME and peripheral immune population recapitulate those observed during AS. Specifically, we want to test if methotrexate plus vinorelbine can induce changes in the peripheral immune population making patient peripheral immune profile similar to that of patients who experience spontaneous regression during AS. To test this hypothesis, we will conduct a prospective observation study to collect tissue and blood samples from patients on first-line treatment with methotrexate and vinorelbine. We expect that our findings by integrating data from patients who undergo spontaneous regression during AS with data from patients experiencing response to systemic treatments, will further show how the immune system contributes to tumor control and regression.
Scientific Abstract
Sporadic desmoid-type fibromatosis (DF) is a rare, locally aggressive mesenchymal tumor with an unpredictable clinical course. While some patients experience spontaneous regression (REG) under active surveillance (AS), others progress (PROG) and require treatment. In a recent prospective study at our institution, we analyzed the immune landscape in DF patients under AS and identified distinct immune profiles associated with diverse clinical outcomes. These findings globally suggest that immune homeostasis plays a central role in modulating DF behavior, promoting pro-resolving immunity in REG while instead sustaining a pro-inflammatory, pro-fibrotic phenotype in PROG.
Notably, these immune signatures can be detected in peripheral blood, offering potential for novel biomarkers to predict disease course and enable patient-tailored interventions.
Building on these insights, we propose a translational research project aimed at further dissecting the immune mechanisms underlying both spontaneous and treatment-induced regression in DF patients enrolled in a newly activated prospective international multicenter study, partially funded by an institutional grant. Specifically, we will:
1. Evaluate baseline and longitudinal blood samples to quantify and profile pro-resolving versus pro-inflammatory immune responses in both spontaneous and treatment-induced regression, compared to progression.
2. To deeply characterize immune cell populations within desmoid tumor tissue using spatial omic approaches and define their interactions with tumor cells in the TIME, with the goal of associating specific immune compositions with disease outcome (progression vs. regression).
3. Apply statistical approaches to integrate findings from Aim1 with clinical and tumor data (i.e. β-catenin mutation), as well as with systemic immune profile of patients under AS to identify common mechanisms of spontaneous and therapy-induced regression.
This comprehensive approach will enhance our understanding of DF immunopathogenesis and facilitate the development of targeted immunomodulatory strategies.
