British Journal of Cancer

Vermeulen, Peter; Latacz, Emily; Hendrickx, Laura; Van den Hauwe, Michelle; Dirix, Luc

doi: 10.1038/s41416-023-02173-6pmid: 36717676

van der Kooij, Monique K.; Joosse, Arjen; Suijkerbuijk, Karijn P. M.; Aarts, Maureen J. B.; van den Berkmortel, Franchette W. P. J.; Blank, Christian U.; Boers-Sonderen, Marye J.; van den Eertwegh, Alfonsus J. M.; de Groot, Jan Willem B.; Haanen, John B. A. G.; Hospers, Geke A. P.; Piersma, Djura; van Rijn, Rozemarijn S.; van der Veldt, Astrid A. M.; Vreugdenhil, Gerard; Westgeest, Hans M.; Wouters, Michel W. J. M.; Dekkers, Olaf M.; Kapiteijn, Ellen

doi: 10.1038/s41416-022-02088-8

Ferreira, Miguel R.; Andreyev, Jervoise N.; Wedlake, Linda; Dearnaley, David P.

doi: 10.1038/s41416-023-02163-8pmid: 36717675

Canas-Marques, Rita; Schnitt, Stuart J.

doi: 10.1038/s41416-023-02152-xpmid: 36707635

Liu, Senbo; Zhang, Yan; Liu, Yang; Wang, Wenkang; Gao, Shuochen; Yuan, Weitang; Sun, Zhenqiang; Liu, Lin; Wang, Chengzeng

doi: 10.1038/s41416-022-02076-ypmid: 36463323

Cancer immunotherapy (CIT) has gained increasing attention and made promising progress in recent years, especially immune checkpoint inhibitors such as antibodies blocking programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, its therapeutic efficacy is only 10–30% in solid tumours and treatment sensitivity needs to be improved. The complex tissue environment in which cancers originate is known as the tumour microenvironment (TME) and the complicated and dynamic TME is correlated with the efficacy of immunotherapy. Ultrasound-targeted microbubble destruction (UTMD) is an emerging technology that integrates diagnosis and therapy, which has garnered much traction due to non-invasive, targeted drug delivery and gene transfection characteristics. UTMD has also been studied to remodel TME and improve the efficacy of CIT. In this review, we analyse the effects of UTMD on various components of TME, including CD8+ T cells, tumour-infiltrating myeloid cells, regulatory T cells, natural killer cells and tumour vasculature. Moreover, UTMD enhances the permeability of the blood-brain barrier to facilitate drug delivery, thus improving CIT efficacy in vivo animal experiments. Based on this, we highlight the potential of immunotherapy against various cancer species and the clinical application prospects of UTMD.

Abildgaard, Amanda B.; Nielsen, Sofie V.; Bernstein, Inge; Stein, Amelie; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus

doi: 10.1038/s41416-022-02059-zpmid: 36434153

Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system. Loss-of-function variants disrupt the DNA mismatch repair system and give rise to a detrimental increase in the cellular mutational burden and cancer development. The treatment prospects for Lynch syndrome rely heavily on early diagnosis; however, accurate diagnosis is inextricably linked to correct clinical interpretation of individual variants. Protein variant classification traditionally relies on cumulative information from occurrence in patients, as well as experimental testing of the individual variants. The complexity of variant classification is due to (1) that variants of unknown significance are rare in the population and phenotypic information on the specific variants is missing, and (2) that individual variant testing is challenging, costly and slow. Here, we summarise recent developments in high-throughput technologies and computational prediction tools for the assessment of variants of unknown significance in Lynch syndrome. These approaches may vastly increase the number of interpretable variants and could also provide important mechanistic insights into the disease. These insights may in turn pave the road towards developing personalised treatment approaches for Lynch syndrome.

Baker, Kevin James; Brint, Elizabeth; Houston, Aileen

doi: 10.1038/s41416-022-02083-zpmid: 36482185

BackgroundThe interleukin (IL)-36 cytokines are a sub-family of the IL-1 family which are becoming increasingly implicated in the pathogenesis of inflammatory diseases and malignancies. Initial studies of IL-36 signalling in tumorigenesis identified an immune-mediated anti-tumorigenic function for these cytokines. However, more recent studies have shown IL-36 cytokines also contribute to the pathogenesis of lung and colorectal cancer (CRC).MethodsThe aim of this study was to investigate IL-36 expression in CRC using transcriptomic datasets and software such as several R packages, Cytoscape, GEO2R and AnalyzeR. Validation of results was completed by qRT-PCR on both cell lines and a patient cohort. Cellular proliferation was assessed by flow cytometry and resazurin reduction.ResultsWe demonstrate that IL-36 gene expression increases with CRC development. Decreased tumoral IL-36 receptor expression was shown to be associated with improved patient outcome. Our differential gene expression analysis revealed a novel role for the IL-36/IL-17/IL-23 axis, with these findings validated using patient-derived samples and cell lines. IL-36γ, together with either IL-17a or IL-22, was able to synergistically induce different genes involved in the IL-17/IL-23 axis in CRC cells and additively induce colon cancer cell proliferation.ConclusionsCollectively, this data support a pro-tumorigenic role for IL-36 signalling in colon cancer, with the IL-17/IL-23 axis influential in IL-36-mediated colon tumorigenesis.

Zhang, Xuexi; Wang, Hao; Liu, Wenxu; Xiao, Zengtuan; Ma, Zhenyi; Zhang, Zhenfa; Gong, Wenchen; Chen, Jun; Liu, Zhe

doi: 10.1038/s41416-022-02103-ypmid: 36517551

BackgroundSmall cell lung cancer (SCLC) is the most aggressive subtype of lung cancer without recognised morphologic or genetic heterogeneity. Based on the expression of four transcription factors, ASCL1, NEUROD1, POU2F3, and YAP1, SCLCs are classified into four subtypes. However, biological functions of these different subtypes are largely uncharacterised.MethodsWe studied intratumoural heterogeneity of resected human primary SCLC tissues using single-cell RNA-Seq. In addition, we undertook a series of in vitro and in vivo functional studies to reveal the distinct features of SCLC subtypes.ResultsWe identify the coexistence of ASCL1+ and NEUROD1+ SCLC cells within the same human primary SCLC tissue. Compared with ASCL1+ SCLC cells, NEUROD1+ SCLC cells show reduced epithelial features and lack EPCAM expression. Thus, EPCAM can be considered as a cell surface marker to distinguish ASCL1+ SCLC cells from NEUROD1+ SCLC cells. We further demonstrate that NEUROD1+ SCLC cells exhibit higher metastatic capability than ASCL1+ SCLC cells and can be derived from ASCL1+ SCLC cells.ConclusionsOur studies unveil the biology and evolutionary trajectory of ASCL1+ and NEUROD1+ SCLC cells, shedding light on SCLC tumourigenesis and progression.

McGovern, Josh; Dolan, Ross D.; Simmons, Claribel P. L.; Daly, Louise E.; Ryan, Aoife M.; Power, Derek G.; Maguire, Donogh; Fallon, Marie T.; Laird, Barry J.; McMillan, Donald C.

doi: 10.1038/s41416-022-02099-5pmid: 36517550

BackgroundAlthough suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined.MethodsProspectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011–2016, was retrospectively analysed. LDH values were grouped as <250/250–500/>500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis.ResultsA total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p < 0.001), NLR (p < 0.05), mGPS (p < 0.05) and 3-month survival (p < 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p < 0.01), BMI (p < 0.05), skeletal muscle mass (p < 0.01), metastatic disease (p < 0.05), NLR (p < 0.05) and mGPS (p < 0.01).DiscussionLDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

Zhang, Cheng; Wang, Juan; Song, Xiaoye; Yu, Deen; Guo, Baoqiang; Pang, Yaoyu; Yin, Xiaomei; Zhao, Shasha; Deng, Huan; Zhang, Shihua; Deng, Wensheng

doi: 10.1038/s41416-022-02098-6pmid: 36526675