bims-tumhet 2022-09-18 papers

Issue of 2022–09–18
seven papers selected by
Sergio Marchini, Humanitas Research

Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00385-3. [Epub ahead of print]40(9): 895-900

Ana C Anderson, Itai Yanai, Lucy R Yates, Linghua Wang, Alexander Swarbrick, Peter Sorger, Sandro Santagata, Wolf H Fridman, Qiang Gao, Livnat Jerby, Benjamin Izar, Lulu Shang, Xiang Zhou.

Spatial transcriptomics, with other spatial technologies, has enabled scientists to dissect the organization and interaction of different cell types within the tumor microenvironment. We asked experts to discuss some aspects of this technology from revealing the tumor microenvironment and heterogeneity, to tracking tumor evolution, to guiding tumor therapy, to current technical challenges.

DOI: https://doi.org/10.1016/j.ccell.2022.08.021

Clin Cancer Res. 2022 Sep 12. pii: CCR-22-2365. [Epub ahead of print]

Multi-omics uncovering different faces of Clear Cell Ovarian Cancer.

Stephanie Lheureux.

The diagnosis of Clear Cell Ovarian Cancer relies on expert histopathology review. Further characterization from deep genomic and transcriptomic analyses can identify different subgroups. International collaboration is required to define the clinical impact and therapy opportunities in these specific sub-classifications.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2365

Nat Rev Cancer. 2022 Sep 15.

Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation.

Lana E Kandalaft, Denarda Dangaj Laniti, George Coukos.

Treatment of high-grade serous ovarian cancer (HGSOC) remains challenging. Although HGSOC can potentially be responsive to immunotherapy owing to endogenous immunity at the molecular or T cell level, immunotherapy for this disease has fallen short of expectations to date. This Review proposes a working classification for HGSOC based on the presence or absence of intraepithelial T cells, and elaborates the putative mechanisms that give rise to such immunophenotypes. These differences might explain the failures of existing immunotherapies, and suggest that rational therapeutic approaches tailored to each immunophenotype might meet with improved success. In T cell-inflamed tumours, treatment could focus on mobilizing pre-existing immunity and strengthening the activation of T cells embedded in intraepithelial tumour myeloid niches. Conversely, in immune-excluded and immune-desert tumours, treatment could focus on restoring inflammation by reprogramming myeloid cells, stromal cells and vascular epithelial cells. Poly(ADP-ribose) polymerase (PARP) inhibitors, low-dose radiotherapy, epigenetic drugs and anti-angiogenesis therapy are among the tools available to restore T cell infiltration in HGSOC tumours and could be implemented in combination with vaccines and redirected T cells.

DOI: https://doi.org/10.1038/s41568-022-00503-z

Front Pharmacol. 2022 ;13 967633

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies.

Nannan Wang, Yan Yang, Dongdong Jin, Zhenan Zhang, Ke Shen, Jing Yang, Huanhuan Chen, Xinyue Zhao, Li Yang, Huaiwu Lu.

Breast cancer and gynecological tumors seriously endanger women's physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

Keywords: ATR/CHK1/WEE1 pathway; PARP inhibitor; PARP inhibitor resistance; breast cancer; combination therapy; gynecological cancer; targeted drugs

DOI: https://doi.org/10.3389/fphar.2022.967633

Front Oncol. 2022 ;12 971959

Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy.

Charleen M L Chan Wah Hak, Antonio Rullan, Emmanuel C Patin, Malin Pedersen, Alan A Melcher, Kevin J Harrington.

Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering pro-inflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This two-pronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)-like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors.

Keywords: DNA damage; cancer therapy; combination therapy; immunotherapy; innate immunity; radiotherapy

DOI: https://doi.org/10.3389/fonc.2022.971959

Cancer Immunol Res. 2022 Sep 12. pii: CIR-22-0407. [Epub ahead of print]

The tumour microenvironment of clear cell ovarian cancer.

Michael-John Devlin, Rowan Miller, Florian Laforets, Panoraia Kotantaki, Dale W Garsed, Rebecca Kristeleit, David D Bowtell, Jacqueline McDermott, Eleni Maniati, Frances R Balkwill.

Some patients with advanced clear cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from forty-five patients, nine with FIGO stage I/II (early CCOC) and thirty-six with FIGO stage III/IV (advanced CCOC). We investigated fourteen immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray dataset from a second cohort of twenty-nine patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared to early-CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating "TGFβ remodeling of the extracellular matrix" as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0407

Front Pharmacol. 2022 ;13 958146

Emerging role of different DNA methyltransferases in the pathogenesis of cancer.

Pengcheng Liu, Fan Yang, Lizhi Zhang, Ying Hu, Bangjie Chen, Jianpeng Wang, Lei Su, Mingyue Wu, Wenjian Chen.

DNA methylation is one of the most essential epigenetic mechanisms to regulate gene expression. DNA methyltransferases (DNMTs) play a vital role in DNA methylation in the genome. In mammals, DNMTs act with some elements to regulate the dynamic DNA methylation patterns of embryonic and adult cells. Conversely, the aberrant function of DNMTs is frequently the hallmark in judging cancer, including total hypomethylation and partial hypermethylation of tumor suppressor genes (TSGs), which improve the malignancy of tumors, aggravate the ailment for patients, and significantly exacerbate the difficulty of cancer therapy. Since DNA methylation is reversible, currently, DNMTs are viewed as an important epigenetic target for drug development. However, the impression of DNMTs on cancers is still controversial, and therapeutic methods targeting DNMTs remain under exploration. This review mainly summarizes the relationship between the main DNMTs and cancers as well as regulatory mechanisms and clinical applications of DNMTs in cancer and highlights several forthcoming strategies for targeting DNMTs.

Keywords: DNMT; anticancer therapy; cancer; cellular signaling pathways; epigenetics

DOI: https://doi.org/10.3389/fphar.2022.958146