T‐cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death‐ligand 1 expression in patients with soft tissue sarcomas

Abstract

BACKGROUNDPatients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited.METHODSThe authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well‐differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD‐1) and programmed death‐ligand 1 (PD‐L1), and T‐cell receptor Vβ gene sequencing were performed on formalin‐fixed, paraffin‐embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated.RESULTSUPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T‐cell infiltration. UPS were found to have higher levels of PD‐L1 (P≤.001) and PD‐1 (P≤.05) on immunohistochemistry and had the highest T‐cell infiltration based on T‐cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T‐cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T‐cell infiltration and clonality were highly correlated with PD‐1 and PD‐L1 expression levels (P≤.01).CONCLUSIONSIn the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self‐antigens, and therefore strategies to improve antigen presentation and T‐cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291‐304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens

“…Numerous studies have evaluated the expression of PD‐L1 in DSRCT and synovial sarcoma with conflicting results. While some authors reported high levels of PD‐L1 in DSRCT tissue and in synovial sarcoma, in contrast, and consistent with our findings, two other groups reported very low or no expression of PD‐L1 in either tumor type . We observed extensive heterogeneity of PD‐L1 expression within each tumor type, which might explain the disparate reports.…”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…In many cases, sarcomas epitomize the most challenging obstacles to overcome in facilitating an immune response. While understanding of the sarcoma immune TME is limited, available data suggest that sarcomas are likely to be cold tumors, with relatively infrequent expression of PD‐L1, low mutational burden, and suppressive immune infiltrates consisting of suppressive macrophages and myeloid derived suppressor cells (MDSCs), rather than exhausted CD8 + T cells . To develop hypotheses for immunotherapy strategies likely to improve responses for resistant sarcomas, we will now examine current and future efforts that aim to build upon immune checkpoint blockade.…”

Immunotherapy in tumors failing check-point inhibitors:the sarcoma example – What we missed and where we are heading

“…As for other tumors types, sarcoma histotypes can be differentiated into "hot-inflamed" or "cold not-inflamed" tumors and these features, as already mentioned, seem to be an approximate predictive biomarker for response to immunotherapies [10,28]. Cold tumors display a completely different immunobiologic signature: lack of type I interferon signature, lack of chemokines for recruitment of T cells, lack of T cells infiltrate, vasculature non-permissive for T cells entry etc.…”

“…This heterogeneity is both a challenge and an intriguing model for the study of finetuning mechanisms of the TME. For instance, in a recent paper [10] and their different lymphocytic infiltrate. The authors found a positive correlation between mutational burden, immunogenicity, an abundance of oligoclonal T-cell infiltrates and the great variability of the microenvironmental immune asset among histotypes.…”

“…The second one, is that high mutational burden has been correlated with response to immunotherapy, but may not be sufficient to cause a relevant clinical benefit, for example, a clinically significant improvement in progression-free survival (PFS). Indeed, data recently presented at the American Society of Clinical Oncology (ASCO) annual meeting from a phase II study of pembrolizumab, in a cohort of patients with advanced soft-tissue or bone sarcoma (SARC028), demonstrated that high mutational burden sarcomas, UPS and LMS, obtained different clinical response rates (40% of overall response rate in UPS cohort and 0% in LMS cohort) suggesting a more complex interaction between mutational burden, TME and IS leading to a greater variability of behavior between different histotypes [10,28].…”