Intratumoral immune-biomarkers and mismatch repair status in leiyomyosarcoma -potential predictive markers for adjuvant treatment: a pilot study

Cohen, Jonathan; Eleyan, Feras; Zick, Aviad; Peretz, Tamar; Katz, Daniela

doi:10.18632/oncotarget.25747

Cited by 12 publications

(13 citation statements)

References 35 publications

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“…Cohen et al ., have recently shown in a small cohort of 11 LMS cases that CD3+ TILs were present in both the central (11/11) and periphery (9/9) regions of the tumour. In their study, CD8+ TILs were found in a subset of cases in the central (10/11) and periphery (7/9) of the tumour 41 . Given the small number of cases assessed in both studies, further evidence in larger cohorts is required to determine if these observations are generally applicable to LMS and other STS subtypes.…”

Section: Discussionmentioning

confidence: 88%

The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma

Lee

Chew

Wilding

et al. 2019

Sci Rep

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The characterisation and clinical relevance of tumour-infiltrating lymphocytes (TILs) in leiomyosarcoma (LMS), a subtype of soft tissue sarcoma that exhibits histological heterogeneity, is not established. The use of tissue microarrays (TMA) in studies that profile TIL burden is attractive but given the potential for intra-tumoural heterogeneity to introduce sampling errors, the adequacy of this approach is undetermined. In this study, we assessed the histological inter- and intra-tumoural heterogeneity in TIL burden within a retrospective cohort of primary LMS specimens. Using a virtual TMA approach, we also analysed the optimal number of TMA cores required to provide an accurate representation of TIL burden in a full tissue section. We establish that LMS have generally low and spatially homogenous TIL burdens, although a small proportion exhibit higher levels and more heterogeneous distribution of TILs. We show that a conventional and practical number (e.g. ≤3) of TMA cores is adequate for correct ordinal categorisation of tumours with high or low TIL burden, but that many more cores (≥11) are required to accurately estimate absolute TIL numbers. Our findings provide a benchmark for the design of future studies aiming to define the clinical relevance of the immune microenvironments of LMS and other sarcoma subtypes.

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Section: Discussionmentioning

confidence: 88%

The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma

Lee

Chew

Wilding

et al. 2019

Sci Rep

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“…However, few models have been proposed to predict the prognosis of LMS. Cohen et al observed the association between tumor infiltrating CD8 cytotoxic lymphocytes, PD-L1 staining, expression of mismatch repair-related proteins (MSH2, MLH1, MSH6 and PSM2) and survival in patients with LMS [ 54 ]. Studies from Xue et al suggested that age greater than 60 years, high tumor grade, distant metastasis, tumor size ≥ 5 cm, and lack of surgery were associated with decreased OS and cancer-specific survival [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma

Huang

Lai

et al. 2021

J Biomed Sci

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Background Leiomyosarcoma (LMS), the most common soft tissue sarcoma, exhibits heterogeneous and complex genetic karyotypes with severe chromosomal instability and rearrangement and poor prognosis. Methods Clinical variables associated with NKX6-1 were obtained from The Cancer Genome Atlas (TCGA). NKX6-1 mRNA expression was examined in 49 human uterine tissues. The in vitro effects of NXK6-1 in LMS cells were determined by reverse transcriptase PCR, western blotting, colony formation, spheroid formation, and cell viability assays. In vivo tumor growth was evaluated in nude mice. Results Using The Cancer Genome Atlas (TCGA) and human uterine tissue datasets, we observed that NKX6-1 expression was associated with poor prognosis and malignant potential in LMS. NKX6-1 enhanced in vitro tumor cell aggressiveness via upregulation of cell proliferation and anchorage-independent growth and promoted in vivo tumor growth. Moreover, overexpression and knockdown of NKX6-1 were associated with upregulation and downregulation, respectively, of stem cell transcription factors, including KLF8, MYC, and CD49F, and affected sphere formation, chemoresistance, NOTCH signaling and Sonic hedgehog (SHH) pathways in human sarcoma cells. Importantly, treatment with an SHH inhibitor (RU-SKI 43) but not a NOTCH inhibitor (DAPT) reduced cell survival in NKX6-1-expressing cancer cells, indicating that an SHH inhibitor could be useful in treating LMS. Finally, using the TCGA dataset, we demonstrated that LMS patients with high expression of NKX6-1 and HHAT, an SHH pathway acyltransferase, had poorer survival outcomes compared to those without. Conclusions Our findings indicate that NKX6-1 and HHAT play critical roles in the pathogenesis of LMS and could be promising diagnostic and therapeutic targets for LMS patients.

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“…Studies on DDLPS and pleomorphic liposarcomas [41,64], myxofibrosarcoma [38,41], fibrosarcoma [41], desmoplastic small round cell tumor [29,66], osteosarcoma [38,58,64,67], UPS [38,64], and pleomorphic dermal sarcoma [39] report less than half the cases show PD-L1 expression on the sarcoma cells. In comparison, PD-L1 was expressed on the neoplastic cells in more than half of leiomyosarcoma [35,37,41] and giant cell tumor specimens [58].…”

Section: Pd-l1mentioning

confidence: 96%

“…A majority of studies find CD8+ T cells to be more abundant [11,[32][33][34] relative to FOXP3+ T regulatory cells [32][33][34][35][36]. When divided based on karyotype complexity, copy number-driven sarcomas (DDLPS [11], leiomyosarcoma [35,37], UPS, and myxofibrosarcoma [38]) had higher T cell infiltration than translocation-associated subtypes [11]. In rhabdomyosarcomas, the copy number-and mutationdriven embryonal subtype has more CD3+ and CD8+ T cell infiltration than its translocation-associated counterpart, alveolar rhabdomyosarcoma [36].…”

Section: T Cell Infiltration: Cd3 Cd4 Cd8 Foxp3mentioning

confidence: 99%

“…Apparent rates of positivity may also be hard to compare between IHC studies due to differences between antibody clones produced by different companies, staining platforms, staining conditions, interpretation and cutpoints for defining a case as positive [114]. In sarcoma cell lines [64] and leiomyosarcoma tumors [37], clone 22C3 (Dako) showed less staining than clone SP142 and clone 28-8 (Abcam #ab205921), respectively. Centralized protocols for quantification of PD-L1 expression should be considered in sarcoma, similar to those established in lung cancer [114].…”

Section: Limitations Of Published Studiesmentioning

confidence: 99%

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Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Zhu

Shenasa

Nielsen

2020

Cancer Treatment Reviews

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Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an "immune cold" tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas.Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.

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Intratumoral immune-biomarkers and mismatch repair status in leiyomyosarcoma -potential predictive markers for adjuvant treatment: a pilot study

Cited by 12 publications

References 35 publications

The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma

The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma

NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

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