Sarcoma Common MHC-I Haplotype Restricts Tumor-Specific CD8+ T Cell Response

Mosca, Laura; Angelis, Alessandra De; Ronchi, Andrea; Chiara, Annarosaria De; Fazioli, Flavio; Ruosi, Carlo; Altucci, Lucia; Conte, Mariarosaria; Nigris, Filomena de

doi:10.3390/cancers14143414

Cited by 8 publications

(8 citation statements)

References 43 publications

(56 reference statements)

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“…One mechanism contributing to the immunosuppressive effect of the TME is the downregulation of the HLA immunophenotype inhibiting CD8 + cell activation following PD-1/PD-L1 treatment [65]. However, clinical studies reported responses to ICIs in only a few sarcoma entities [66].…”

Section: Current Immunotherapy and Clinical Resultsmentioning

confidence: 99%

Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy

de Nigris,

Meo,

Palinski

2023

Cells

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Genomic-based precision medicine has not only improved tumour therapy but has also shown its weaknesses. Genomic profiling and mutation analysis have identified alterations that play a major role in sarcoma pathogenesis and evolution. However, they have not been sufficient in predicting tumour vulnerability and advancing treatment. The relative rarity of sarcomas and the genetic heterogeneity between subtypes also stand in the way of gaining statistically significant results from clinical trials. Personalized three-dimensional tumour models that reflect the specific histologic subtype are emerging as functional assays to test anticancer drugs, complementing genomic screening. Here, we provide an overview of current target therapy for sarcomas and discuss functional assays based on 3D models that, by recapitulating the molecular pathways and tumour microenvironment, may predict patient response to treatments. This approach opens new avenues to improve precision medicine when genomic and pathway alterations are not sufficient to guide the choice of the most promising treatment. Furthermore, we discuss the aspects of the 3D culture assays that need to be improved, such as the standardisation of growth conditions and the definition of in vitro responses that can be used as a cut-off for clinical implementation.

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Section: Current Immunotherapy and Clinical Resultsmentioning

confidence: 99%

Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy

de Nigris,

Meo,

Palinski

2023

Cells

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“…This finding was further strengthened with significant correlations between CD3 + T and CD8 + T cells with MHC-I, while NK cells did not show an association. Downregulation of MHC-I in multiple cancers, including STS, is a well-established mechanism of evasion of the immune system, especially that of cytotoxic CD8 + T cells (45)(46)(47)(48). However, these effects may have regional roles in the TME.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral NKp46+ natural killer cells are spatially distanced from T and MHC-I+ cells with prognostic implications in soft tissue sarcoma

et al. 2023

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IntroductionSoft tissue sarcomas (STS) are rare, heterogenous malignancies with an unmet need for novel immunotherapies. Tumor infiltrating lymphocytes (TILs) have been linked with favorable outcomes in STS patients, though the contribution of natural killer (NK) cells and spatial relationships of TILs with MHC-I expressing cells lacks detailed characterization.Experimental designUsing archived and prospectively collected specimens, we evaluated intratumoral NK cells by immunohistochemistry (IHC), flow cytometry, and immunofluorescence (IF). We assessed spatial localization of NK and T cells by multiplex IF, analyzing the effects of MHC-I expression status on NK and T cell clustering.ResultsBoth intratumoral NKp46 and CD56dim expression were associated with significantly improved overall survival (P=0.05), while higher infiltrates of CD56bright NK cells predicted a worse prognosis (P=0.05). The presence of intratumoral NK cells was inversely proportional to CD3+ T cells. Spatial analyses showed NK cells preferentially clustering close to other NK cells with sparse CD3+ T and CD8+ T cells in range (P<0.0001). Additionally, CD3+ T and CD8+ T cells showed significantly greater co-localization with MHC-I+ cells, compared to NK cells (P<0.0001). After neoadjuvant radiotherapy, there was greater CD8 clustering, while after neoadjuvant chemotherapy, there was overall lower TIL clustering.ConclusionIntratumoral NK cells are prognostic in STS and localize closer to MHC-I- cells than T cells. Although both NK and T cells are associated with improved survival in STS, their differential distribution in the TME based on MHC-I expression status may serve as a biomarker for improved immunotherapy treatment selection.

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“…A very recent study showed the STC2-mediated down-regulation of MHC-I molecules in osteosarcoma as a mechanism to achieve immune evasion by suppressing type II interferon response and reducing CD8+ T cells infiltration (53). In addition, a reduction of both HLA-A and HLA-B genes was reported also in UPS, MFS, LMS, Undifferentiated sarcoma and MLPS compared to respective healthy tissue (54). Interestingly, the down-regulation of class I MHC mediated antigen processing in MFS and UPS patients has been recently correlated with anthracycline resistance of patientderived primary cultures (55).…”

Section: The Clinical (And Translational) Relevance Of Tumor Immune M...mentioning

confidence: 93%

Clinical and translational implications of immunotherapy in sarcomas

Recine,

Vanni,

Bongiovanni

et al. 2024

Front. Immunol.

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Immunotherapy has emerged as promising treatment in sarcomas, but the high variability in terms of histology, clinical behavior and response to treatments determines a particular challenge for its role in these neoplasms. Tumor immune microenvironment (TiME) of sarcomas reflects the heterogeneity of these tumors originating from mesenchymal cells and encompassing more than 100 histologies. Advances in the understanding of the complexity of TiME have led to an improvement of the immunotherapeutic responsiveness in sarcomas, that at first showed disappointing results. The proposed immune-classification of sarcomas based on the interaction between immune cell populations and tumor cells showed to have a prognostic and potential predictive role for immunotherapies. Several studies have explored the clinical impact of immune therapies in the management of these histotypes leading to controversial results. The presence of Tumor Infiltrating Lymphocytes (TIL) seems to correlate with an improvement in the survival of patients and with a higher responsiveness to immunotherapy. In this context, it is important to consider that also immune-related genes (IRGs) have been demonstrated to have a key role in tumorigenesis and in the building of tumor immune microenvironment. The IRGs landscape in soft tissue and bone sarcomas is characterized by the connection between several tumor-related genes that can assume a potential prognostic and predictive therapeutic role. In this paper, we reviewed the state of art of the principal immune strategies in the management of sarcomas including their clinical and translational relevance.

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Sarcoma Common MHC-I Haplotype Restricts Tumor-Specific CD8+ T Cell Response

Cited by 8 publications

References 43 publications

Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy

Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy

Intratumoral NKp46+ natural killer cells are spatially distanced from T and MHC-I+ cells with prognostic implications in soft tissue sarcoma

Clinical and translational implications of immunotherapy in sarcomas

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