Cancer Testis Antigens and Immunotherapy: Where Do We Stand in the Targeting of PRAME?

Al-Khadairi, Ghaneya; Decock, Julie

doi:10.3390/cancers11070984

Cited by 85 publications

(76 citation statements)

References 83 publications

(115 reference statements)

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“…Two main therapeutic approaches in PRAME-targeted therapy include cancer vaccines and adoptive T cell therapy. The status of finished and ongoing clinical trials targeting PRAME has been recently reviewed [ 83 ]. This includes a phase 1/2 dose-finding and -expansion trial for mUM patients that commenced in 2017 whereby participants’ T-cells are modified to recognize and target PRAME ( ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Krishna

Acha-Sagredo

Sabat-Pośpiech

et al. 2020

Cancers

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Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an “immunoscore” (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver; intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p < 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases; LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Krishna

Acha-Sagredo

Sabat-Pośpiech

et al. 2020

Cancers

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“…Given that PRAME expression was negatively correlated with lymphocyte infiltration in our study and that PRAME has been described to downregulate antigen-presentation [22], effective strategies for T-cell recruitment and activation will be needed. These may include a boost of MHC class I expression using, e.g., demethylating drugs and other approaches [23], combinatorial therapy with NK cells [24], or checkpoint inhibitors [25].…”

Section: Discussionmentioning

confidence: 99%

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma

Albertsmeier

Altendorf-Hofmann

Lindner

et al. 2020

Cancers

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(1) Background: PRAME, NY-ESO-1, and SSX2 are cancer testis antigens (CTAs), which are expressed in testicular germ cells with re-expression in numerous cancer types. Their ability to elicit humoral and cellular immune responses have rendered them promising targets for cancer immunotherapy, but they have never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: On a protein level, we examined PRAME, NY-ESO-1, and SSX2 expression in tumour tissues of 249 high-risk STS using immunohistochemistry. We correlated expression levels with clinicopathological parameters including tumour-infiltrating lymphocyte (TIL) counts, grading, and long-term survival. (3) Results: Expression of PRAME, NY-ESO-1, and SSX2 was observed in 25 (10%), 19 (8%), and 11 (4%) of 249 specimens with distinct patterns for histo-subtypes. Expression of PRAME was associated with shorter patient survival (p = 0.005) and higher grade (G2 vs. G3, p = 0.001), while NY-ESO-1 expression was correlated with more favourable survival (p = 0.037) and lower grade (G2 vs. G3, p = 0.029). Both PRAME and NY-ESO-1 expression were more frequent in STS with low TIL counts. In multivariate analysis, high PRAME and low SSX2 expression levels as well as metastatic disease and non-radical resections were independent predictors of shorter overall survival. (4) Conclusions: CTAs PRAME, NY-ESO-1, and SSX2 show distinct expression patterns in different STS subtypes. These results demonstrate their prognostic relevance and may guide future immunotherapeutic approaches in STS.

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“…Cancer testis antigens are gaining interest as targets for adoptive T cell therapy with numerous preclinical studies and clinical trials focusing on NY-ESO-1, MAGE-A3 and PRAME [30][31][32]. To date, there are no published data on the immunogenicity and targetability of the cancer testis antigen LDHC for cancer immunotherapy except for a Master's thesis that is deposited in the public domain [33].…”

Section: Discussionmentioning

confidence: 99%

“…The potential existence of an expression threshold for an effective anti-tumor response has important implications for LDHC-specific immunotherapy. In accordance, current efforts are directed towards increasing the expression of CTAs, including NY-ESO-1 and PRAME, through combination treatment of demethylating agents and histone deacetylase inhibitors [30,32]. Using this combination treatment, both the intra-tumor heterogeneous expression of CTAs and the expression threshold could be addressed.…”

Section: Discussionmentioning

confidence: 99%

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

Thomas

Shaath

Belič

et al. 2020

Cancer Immunol Immunother

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Lactate dehydrogenase C (LDHC) is an archetypical cancer testis antigen with limited expression in adult tissues and reexpression in tumors. This restricted expression pattern together with the important role of LDHC in cancer metabolism renders LDHC a potential target for immunotherapy. This study is the first to investigate the immunogenicity of LDHC using T cells from healthy individuals. LDHC-specific T cell responses were induced by in vitro stimulation with synthetic peptides, or by priming with autologous peptide-pulsed dendritic cells. We evaluated T cell activation by IFN-γ ELISpot and determined cytolytic activity of HLA-A*0201-restricted T cells in breast cancer cell co-cultures. In vitro T cell stimulation induced IFN-γ secretion in response to numerous LDHC-derived peptides. Analysis of HLA-A*0201 responses revealed a significant T cell activation after stimulation with peptide pools 2 (PP2) and 8 (PP8). The PP2-and PP8-specific T cells displayed cytolytic activity against breast cancer cells with endogenous LDHC expression within a HLA-A*0201 context. We identified peptides LDHC 41−55 and LDHC 288−303 from PP2 and PP8 to elicit a functional cellular immune response. More specifically, we found an increase in IFN-γ secretion by CD8 + T cells and cancer-cell-killing of HLA-A*0201/LDHC positive breast cancer cells by LDHC 41−55-and LDHC 288−303-induced T cells, albeit with a possible antigen recognition threshold. The majority of induced T cells displayed an effector memory phenotype. To conclude, our findings support the rationale to assess LDHC as a targetable cancer testis antigen for immunotherapy, and in particular the HLA-A*0201 restricted LDHC 41-55 and LDHC 288-303 peptides within LDHC.

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Cancer Testis Antigens and Immunotherapy: Where Do We Stand in the Targeting of PRAME?

Cited by 85 publications

References 83 publications

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

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