PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

Abstract

Soft-tissue sarcomas (STS) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. In the quest for new treatments, the immune system represents an attractive therapeutic target. Recently, PD1/PDL1 inhibitors showed very promising results in patients with solid tumors. PDL1 expression has been rarely studied in STS, in small series only, by using immunohistochemistry (IHC), and with non-concordant prognostic implications. Here, we have analyzed PDL1 mRNA expression in 758 clinical STS samples retrospectively profiled using DNA microarrays and RNAseq, and searched for correlations with clinicopathological variables including metastasis-free survival (MFS) after surgery. PDL1 expression was heterogeneous across the samples. PDL1-high samples (41%) were more frequently leiomyosarcomas and liposarcomas, and showed more frequently a complex genetic profile and a high-risk CINSARC signature. No correlation existed with other clinicopathological features such as tumor site, depth, and pathological tumor grade and size. In multivariate prognostic analysis, the PDL1-high class was associated with shorter MFS, independently of the pathological type and the CINSARC signature. Analysis of correlations with biological factors suggested the existence in tumors of the PDL1-high class of a strong and efficient cytotoxic T-cell response, however associated with some degree of T-cell exhaustion and negative regulation. In conclusion, we show that PDL1 expression refines the prediction of metastatic relapse in operated localized STS, and that PD1/PDL1 blockade holds potential to improve patient survival by reactivating inhibited T cells to increase the antitumor immune in PDL1-high tumors.

Integrative analysis of PD‐L1 DNA status, mRNA status and protein status, and their clinicopathological correlation, in diffuse large B‐cell lymphoma

“…Recently, using IHC, numerous studies have reported PD‐L1 protein expression in different types of cancer . Given that PD‐L1 DNA amplification was rare in our study, the expression of PD‐L1 was mainly regulated by many kinds of signalling pathway as a downstream effector instead of an upstream initiator.…”

“…Recently, using IHC, numerous studies have reported PD-L1 protein expression in different types of cancer. [19][20][21] Given that PD-L1 DNA amplification was rare in our study, the expression of PD-L1 was mainly regulated by many kinds of signalling pathway as a downstream effector instead of an upstream initiator. Lu et al found that MLL1 could inhibit PD-L1 mRNA expression by decreasing the level of trimethylation of histone 3 lysine 4 in the PD-L1 promoter.…”

The Biology of Myxofibrosarcoma: State of the Art and Future Perspectives

“…T-cell infiltration and PD-L1 expression were found to be higher in sarcomas with complex genomics and particularly in UPS than in other STS [87, 88]. Among STS subtypes, UPS/MFS has the highest median macrophage infiltration and the infiltration of immature dendritic cells was positively correlated with survival.…”

PD‐L1 expression in tumour microenvironment supports the rationale for immune checkpoint blockade in classic Kaposi's sarcoma

“…On the other hand, the assessment of the action of PD-1/ PD-L1 blockers as well as the prognostic value of PD-1/PD-L1 expression in soft-tissue sarcomas have been studied only in the last years 5 and there is a shortage of studies on PD-1/PD-L1 expression in KS. Furthermore, the results of these studies appear controversial, since Chen et al 6 failed to find cases that expressed detectable PD-L1 among 9 KS patients, while Paydas et al 7 found PD-1 and/or PD-L1 expressed in 80% of KS patients belonging to their case series.…”