Comprehensive Immuno-Molecular Profiles for Liposarcoma: Roles of Programmed Death Ligand 1, Microsatellite Instability, and PIK3CA

Abstract

<b><i>Background:</i></b> Developing personalized strategies for cancer has shown good efficacies. <b><i>Methods:</i></b> We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and <i>PIK3CA</i>. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and <i>PIK3CA</i> mutation/amplification using pyrosequencing and fluorescence in situ hybridization. <b><i>Results:</i></b> Seventeen (23%) cases were TIL<sup>+</sup> (≥1 + expression) and associated with longer 5-year overall survival than those with TIL<sup>–</sup> tumors (84.4 vs. 60.8%, <i>p</i> = 0.007). Six (35.3%) PD-L1<sup>+</sup> tumors were detected only in TIL<sup>+</sup> cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. <i>PIK3CA</i> mutation was detected in 7 (9.5%) [exon 9 (<i>n</i> = 4) and exon 20 (<i>n</i> = 3)] and only 1 Q546K mutation was a PD-L1<sup>+</sup> tumor. <i>PIK3CA</i> copy number gain was detected in 18 (24.4%) and was associated with TIL<sup>+</sup> tumors (<i>p</i> = 0.045). <b><i>Conclusions:</i></b> Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

“…As a whole, LPS seem to be infiltrated by T-cells and express PDL1 ( 63 , 186 ). In regards to separate histotypes of LPS, a general pattern seems to emerge: DDLPS are more infiltrated and express more PDL1, whereas MRLPS seem to be less infiltrated, and WDLPS are probably somewhere in the middle ( 62 , 100 , 107 , 200 ), though the latter has frequently been grouped with DDLPS in reported studies.…”

“…DDLPS and WDLPS seem to have an expression of roughly 10-20% PDL1 ( 62 , 94 , 108 , 200 , 201 ), both in immunohistochemistry and gene expression studies. Compared to other STS, DDLPS seem to be in the higher proportions of TILs and PDL1 expression, though consistently reporting less infiltration than certain subtypes such as UPS ( 62 , 100 , 108 , 202 ).…”

“…Compared to other STS, DDLPS seem to be in the higher proportions of TILs and PDL1 expression, though consistently reporting less infiltration than certain subtypes such as UPS ( 62 , 100 , 108 , 202 ). TILs are present in over 50% of cases ( 61 , 108 , 200 ) with presence of NK cells, B-cells, TLS and expression of co-inhibitory checkpoints such as LAG3 and TIM3 ( 100 , 201 , 203 ). However, T-cell infiltration seems to be less oligoclonal than LMS or UPS ( 62 ).…”

“…MRLPS are poorly infiltrated by T-cells, have a low PDL1, low TCR clonality and are infiltrated by TAMs with a majority of M2 type macrophages ( 62 , 100 ). PDL1 expression is usually less than 10% ( 94 , 200 ). The importance of macrophages and their prognostic value has been reported specifically in MRLPS ( 204 ).…”

Human leukocyte antigen I is significantly downregulated in patients with myxoid liposarcomas

“…It is possible that MLPS tumors express other immune checkpoint molecules that we did not investigate, such as PD-L2 and TIM-3, among many [ 40 ]. Furthermore, although additional biomarkers such as tumor mutation burden, microsatellite instability, and DNA mismatch repair functional status have shown predictive response to immune checkpoint blockade, we did not investigate these biomarkers in this study [ 41 – 43 ].…”