bims-myxlip 2021-04-25 papers

Issue of 2021–04–25
four papers selected by
Laura Mannarino, Humanitas Research

Cancer Immunol Immunother. 2021 Apr 24.

Human leukocyte antigen I is significantly downregulated in patients with myxoid liposarcomas.

Naoki Oike, Hiroyuki Kawashima, Akira Ogose, Hiroshi Hatano, Takashi Ariizumi, Tetsuro Yamagishi, Yudai Murayama, Hajime Umezu, Chihaya Imai, Masanori Hayashi, Naoto Endo.

The characteristics of the tumor immune microenvironment remains unclear in liposarcomas, and here we aimed to determine the prognostic impact of the tumor immune microenvironment across separate liposarcomas subtypes. A total of 70 liposarcoma patients with three subtypes: myxoid liposarcoma (n = 45), dedifferentiated liposarcoma (n = 17), and pleomorphic liposarcoma (n = 8) were enrolled. The presence of tumor infiltrating lymphocytes (CD4+ , CD8+ , FOXP3+ lymphocytes) and CD163+ macrophages and expression of HLA class I and PD-L1 were assessed by immunohistochemistry in the diagnostic samples; overall survival and progression-free survival were estimated from outcome data. For infiltrating lymphocytes and macrophages, dedifferentiated liposarcoma and pleomorphic liposarcoma patients had a significantly higher number than myxoid liposarcoma patients. While myxoid liposarcoma patients with a high number of macrophages were associated with worse overall and progression-free survival, dedifferentiated liposarcoma patients with high macrophage numbers showed a trend toward favorable prognosis. Expression of HLA class I was negative in 35 of 45 (77.8%) myxoid liposarcoma tumors, whereas all dedifferentiated liposarcoma and pleomorphic liposarcoma tumors expressed HLA class I. The subset of myxoid liposarcoma patients with high HLA class I expression had significantly poor overall and progression-free survival, while dedifferentiated liposarcoma patients with high HLA class I expression tended to have favorable outcomes. Only four of 17 (23.5%) dedifferentiated liposarcomas, two of eight (25%) pleomorphic liposarcomas, and no myxoid liposarcoma tumors expressed PD-L1. Our results demonstrate the unique immune microenvironment of myxoid liposarcomas compared to other subtypes of liposarcomas, suggesting that the approach for immunotherapy in liposarcomas should be based on subtype.

Keywords: CD163+ macrophages; Human leukocyte antigen I; Liposarcomas; Prognosis; Programmed death ligand 1; Tumor immune microenvironment

DOI: https://doi.org/10.1007/s00262-021-02928-1

Front Oncol. 2021 ;11 629868

Identification of Novel Prognostic Risk Signatures of Soft Tissue Sarcoma Based on Ferroptosis-Related Genes.

Wenjing Huang, Yuhe Duan, Xiuwei Yang, Cong Shang, Xin Chen, Huanyu Zhang, Fujiang Li.

Background: The role of ferroptosis in tumorigenesis has been confirmed in previous studies. However, the comprehensive analysis of ferroptosis-related gene (FRG) to study the role of FRG in soft tissue sarcoma (STS) is lacking.
Methods: RNA sequencing profile of TCGA-SARC cohort and GTEx were used to select differentially expressed FRGs (DEFRGs). Univariate, LASSO, and multivariate Cox analyses were selected to determine overall survival (OS)- and disease-free survival (PFS)-related FRGs. Two prognostic signatures were established and validated in two independent sets from Gene Expression Omnibus (GEO). Finally, the expression of key FRGs were validated with RT-qPCR.
Results: In total, 198 FRGs (90.4%) were abnormally expressed in STS. Twelve DEFRGs were incorporated in the final signatures and showed favorable discrimination in both training and validation cohorts. Patients in the different risk groups not only showed different prognosis, but also showed different infiltration of immune cells. Two nomograms combining signature and clinical variables were established and the C-indexes were 0.852 and 0.752 for the OS and DFS nomograms, respectively. Finally, the expression of NOX5, HELLS, and RPL8 were validated with RT-qPCR.
Conclusion: This comprehensive analysis of the FRG landscape in STS revealed novel FRGs related to carcinogenesis and prognosis. These findings have implications for prognosis and therapeutic responses, which revealed potential prognostic biomarkers and promote precision medicine.

Keywords: ferroptosis; immune microenvironment; nomogram; signature; soft tissue sarcoma

DOI: https://doi.org/10.3389/fonc.2021.629868

Semin Cell Dev Biol. 2021 Apr 14. pii: S1084-9521(21)00074-4. [Epub ahead of print]

The emerging role of miRNA in the perturbation of tumor immune microenvironment in chemoresistance: Therapeutic implications.

Priya Mondal, Bhavjot Kaur, Jagadish Natesh, Syed Musthapa Meeran.

Chemoresistance is a major hindrance in cancer chemotherapies, a leading cause of tumor recurrence and cancer-related deaths. Cancer cells develop numerous strategies to elude immune attacks and are regulated by immunological factors. Cancer cells can alter the expression of several immune modulators to upregulate the activities of immune checkpoint pathways. Targeting the immune checkpoint inhibitors is a part of the cancer immunotherapy altered during carcinogenesis. These immune modulators have the capability to reprogram the tumor microenvironment, thereby change the efficacy of chemotherapeutics. In general, the sensitivity of drugs is reduced in the immunosuppressive tumor microenvironment, resulting in chemoresistance and tumor relapse. The regulation of microRNAs (miRNAs) is well established in cancer initiation, progression, and therapy. Intriguingly, miRNA affects cancer immune surveillance and immune response by targeting immune checkpoint inhibitors in the tumor microenvironment. miRNAs alter the gene expression at the post-transcriptional level, which modulates both innate and adaptive immune systems. Alteration of tumor immune microenvironment influences drug sensitivity towards cancer cells. Besides, the expression profile of immune-modulatory miRNAs can be used as a potential biomarker to predict the response and clinical outcomes in cancer immunotherapy and chemotherapy. Recent evidences have revealed that cancer-derived immune-modulatory miRNAs might be promising targets to counteract cancer immune escape, thereby increasing drug efficacy. In this review, we have compiled the role of miRNAs in overcoming the chemoresistance by modulating tumor microenvironment and discussed their preclinical and clinical implications.

Keywords: Cancer; Chemoresistance; Immune microenvironment; Tumor immune response; Tumor microenvironment; miRNA-based therapeutics; microRNAs

DOI: https://doi.org/10.1016/j.semcdb.2021.04.001

Nucleic Acids Res. 2021 Apr 22. pii: gkab280. [Epub ahead of print]

Histone sumoylation and chromatin dynamics.

Hong-Yeoul Ryu, Mark Hochstrasser.

Chromatin structure and gene expression are dynamically controlled by post-translational modifications (PTMs) on histone proteins, including ubiquitylation, methylation, acetylation and small ubiquitin-like modifier (SUMO) conjugation. It was initially thought that histone sumoylation exclusively suppressed gene transcription, but recent advances in proteomics and genomics have uncovered its diverse functions in cotranscriptional processes, including chromatin remodeling, transcript elongation, and blocking cryptic initiation. Histone sumoylation is integral to complex signaling codes that prime additional histone PTMs as well as modifications of the RNA polymerase II carboxy-terminal domain (RNAPII-CTD) during transcription. In addition, sumoylation of histone variants is critical for the DNA double-strand break (DSB) response and for chromosome segregation during mitosis. This review describes recent findings on histone sumoylation and its coordination with other histone and RNAPII-CTD modifications in the regulation of chromatin dynamics.

DOI: https://doi.org/10.1093/nar/gkab280