Prognostic impact of the tumor immune microenvironment in synovial sarcoma

Oike, Naoki; Kawashima, Hiroyuki; Ogose, Akira; Hotta, Tomomitsu; Hatano, Hiroshi; Ariizumi, Takashi; Sasaki, Taro; Yamagishi, Tetsuro; Umezu, Hajime; Endo, Naoto

doi:10.1111/cas.13769

Cited by 55 publications

(54 citation statements)

References 48 publications

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“…Across all STS subtypes with ≥6 samples, the rate of PD-1 positive samples in PD-L1 expressing ones was higher than in the negative ones. These results are supported by previous studies in smaller STS cohorts or single STS subtypes demonstrating a PD-L1 and PD-1 interaction 13,14,17,21 , which collectively provide a strong rationale that PD-L1 positive patients are eligible for immune checkpoint inhibitor therapy. Furthermore, our findings support the hypothesis that cancer cells can dynamically increase PD-L1 expression to protect themselves in settings of increased numbers of TILs 12 .…”

Section: Immune Checkpoint Inhibitors Interfering With the Interactiosupporting

confidence: 81%

Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas

Orth¹,

Buecklein

Kampmann

et al. 2019

Preprint

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Section: Immune Checkpoint Inhibitors Interfering With the Interactiosupporting

confidence: 81%

Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas

Orth¹,

Buecklein

Kampmann

et al. 2019

Preprint

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“…SS exhibit minimal leukocyte infiltration [6, 7]. To investigate the tumor immune microenvironment in our patients, we characterized leukocyte infiltration in patient biopsies (Additional file 1: Table S1) taken prior to and following infusion by IHC staining (CD45, CD3, CD4, CD8, CD20, CD163, PD-L1, PD-1, TIM-3, and LAG-3).…”

Section: Resultsmentioning

confidence: 99%

“…PD-1/PD-L1 (programmed cell death) pathway inhibitors have shown durable clinical benefit in tumor histologies that exhibit T-cell infiltration, elevated levels of PD-L1 expression, and higher levels of nonsynonymous somatic mutation burden [5]. By comparison, SS are poorly infiltrated by T cells and have marginal PD-L1 expression [6, 7]. As in other translocation-driven tumors, SS also have a low overall mutational burden.…”

Section: Introductionmentioning

confidence: 99%

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

Ramachandran¹,

Lowther²,

Dryer-Minnerly³

et al. 2019

j. immunotherapy cancer

113

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BackgroundGene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.MethodsFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.ResultsResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.ConclusionsOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.Trial registrationClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

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“…This contrasts with results obtained in other solid tumors 36 and a recent study reporting the poor prognosis of M2-macrophages on a small SS cohort (n = 39) based on CD163 detection by IHC. 37 This M0-macrophage signature may reflect either new monocytes recruited in tumor environment possibly via CCL2/CCR2 pathway to differentiate into M1- or M2-macrophages according to the tumor milieu or an uncommitted precursor of resident macrophages. Targeting CSF-1 receptor to restore the differentiation mechanism of M0-macrophages into dendritic cells could be an interesting therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Specific immune landscapes and immune checkpoint expressions in histotypes and molecular subtypes of sarcoma

et al. 2020

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Soft tissue sarcomas are a group of rare and aggressive connective tissue neoplasms for which curative therapeutic opportunities are limited in advanced phase. Clinical trials assessing immunotherapy in these tumors have so far reported limited efficacy. The objective of this study is to provide a description of the immunologic landscape of sarcomas to guide the next clinical trials of immunotherapy in these diseases. The gene expression profile of 93 immune checkpoint (ICP) and membrane markers (MM) of immune cells was analyzed in a series of 253 soft tissue sarcoma (synovial sarcoma, myxoid liposarcoma, sarcoma with complex genomic and GIST) using Agilent Whole Human Genome Microarrays. The unsupervised hierarchical clustering of gene expression level was found able to properly group patients according to the histological subgroup of sarcoma, indicating that each sarcoma subgroup is associated with a specific immune signature defined by its gene expression pattern. Using the prognostic impact of CIBERSORT signature on metastatic-free survival in each subgroup, specific target could be proposed for each of the four groups: Treg through ICOS and GITR in GIST, M0 macrophages in all four sarcoma subtypes, OX40 in SS, CD40 in GIST and SS. The immune landscape of sarcoma was found to be as heterogeneous as the histotypes and molecular subtypes, but strongly correlated to the histotype. Histotype adapted immunotherapeutic approaches in each sarcoma subtypes must be considered in view of these results, consistently with the already reported specific response of histotypes of ICPs.

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Prognostic impact of the tumor immune microenvironment in synovial sarcoma

Cited by 55 publications

References 48 publications

Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas

Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

Specific immune landscapes and immune checkpoint expressions in histotypes and molecular subtypes of sarcoma

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