Immunologic Gene Signature Analysis Correlates Myeloid Cells and M2 Macrophages with Time to Trabectedin Failure in Sarcoma Patients

SIMPLE SUMMARY: Trabectedin is an FDA-approved chemotherapy with demonstrated benefit for some sarcoma subtypes, particularly in the metastatic setting. Although some patients receiving trabectedin have only modest benefit, other patients are exceptional responders. While several mechanisms of action have been suggested for trabectedin, we suspect that it has a role in immune modulation, and we hypothesized that the presence of specific immune cells and related gene expression patterns may help identify which patients are more likely to benefit from trabectedin therapy. We confirmed that six immunologic gene signatures are significantly associated with up to 7-year survival, notably myeloid-derived suppressor cells and M2 macrophages, using a gene set analysis tool to evaluate group associations. Furthermore, tumors characterized with this type of immunosuppressive microenvironment and high PD-L1 expression are less likely to benefit from trabectedin, which could guide providers in treatment decisions. ABSTRACT: Patients with metastatic soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options. Trabectedin is currently being investigated as a potential adjunct to immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify biomarkers that would be relevant to trials combining trabectedin with immunotherapy. We performed a single-center retrospective study of sarcoma patients treated with trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147 sarcoma patients treated with trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior chemotherapy regimens were more likely to stay on trabectedin longer (pairwise correlation = −0.17, p = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, p = 0.04, q = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells (p = 0.023, q = 0.058) and M2 macrophages (p = 0.03, q = 0.058). We found that the number of chemotherapy regimens prior to trabectedin negatively correlated with the number of trabectedin cycles received, suggesting that patients may benefit from receiving trabectedin earlier in their therapy course. The correlation of trabectedin outcomes with immune cell infiltrates supports the hypothesis that trabectedin may function as an immune modulator and supports ongoing efforts to study trabectedin in combination with immunotherapy. Furthermore, tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from trabectedin, which could guide clinicians in future treatment decisions.