The immune landscape of undifferentiated pleomorphic sarcoma

Abstract

IntroductionUndifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes.Material and methodsSurgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters.ResultsSamples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001).ConclusionWe identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.

Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma

“…UPS constituted the most common subtype of our patients with benign and metastatic LN (27 and 20% respectively). In addition to its heterogeneous and aggressive profile, the immunogenic nature of UPS might be a reason for a high incidence of suspicious LN in this subtype [ 26 ]. However, rare subtypes at high risk for LNM, such as rhabdomyosarcoma, clear cell sarcoma and epithelioid sarcoma were also part of our cohort.…”

Prognostic impact of the post-treatment T cell composition and spatial organization in soft tissue sarcoma patients treated with neoadjuvant hyperthermic radio(chemo)therapy

“…Few studies also employed hierarchical clustering for IHC data. In a cohort of undifferentiated pleomorphic sarcoma, classical IHC staining of T cells, B cells, and macrophages revealed three distinct immune clusters which showed significant differences in regard to OS ( 60 ). Thus, our obtained T cell-based clustering may be extended by staining for additional immune cell markers and can serve to support traditional transcriptomic-based clustering.…”

Multimodal profiling of chordoma immunity reveals distinct immune contextures

“…For instance, we identified abundant CD39 expression on vessels and stromal cells, in the vicinity of immune cells in both T cell high and T cell low chordomas, suggesting that the adenosine pathway might be a potential mediator of immune suppression in chordomas. Although the immunosuppressive functionalities of this pathway have mainly been described in carcinomas 34,35 , expression of CD39 was recently found to associate with increased inflammation in primary tumours as well as with increased T cell densities and PD-1 expression in recurrent undifferentiated soft tissue sarcomas 36 . Further research should determine the extent to which the adenosine pathway can modulate immune responses in this disease.…”