Vessels that encapsulate tumour clusters (VETC) is a distinct histologic vascular pattern associated with a novel mechanism of metastasis. First described in human cancers in 2004, its prevalence and prognostic significance in hepatocellular carcinoma (HCC) has only been appreciated in the past decade with a rapidly increasing body of literature. A robust biomarker of aggressive disease, the VETC pattern is easy to recognise but relies on histologic examination of tumour tissue for its diagnosis. Radiological recognition of the VETC pattern is an area of active research and is becoming increasingly accurate. As a prognostic marker, VETC has consistently proven to be an independent predictor of disease recurrence and overall survival in patients with HCC undergoing resection and liver transplantation. It can also guide treatment by predicting response to other therapies such as transarterial chemoembolisation and sorafenib. Without prospective randomised-controlled trials or routine evaluation of VETC in clinical practice, there are currently no firm treatment recommendations for VETC-positive tumours, although some perspectives are provided in this review based on the latest knowledge of their pathogenesis – a complex interplay between tumour angiogenesis and the immune microenvironment. Nevertheless, VETC has great potential as a future biomarker that could take us one step closer to precision medicine for HCC.

Objectives: SARS‐CoV‐2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T‐cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T‐cell subsets to disease outcome is imperative to inform the development of next‐generation COVID‐19 vaccines.Methods: Immunophenotyping of T‐cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID‐19 clinical presentation. Computational and manual analyses were used to identify T‐cell populations associated with distinct disease states.Results: Critical SARS‐CoV‐2 infection was characterised by an increase in activated and cytotoxic CD4⁺ lymphocytes (CTL). These CD4⁺ CTLs were largely absent in asymptomatic to severe disease states. In contrast, non‐critical COVID‐19 was associated with high frequencies of naïve T cells and lack of activation marker expression.Conclusion: Highly activated and cytotoxic CD4⁺ T‐cell responses may contribute to cell‐mediated host tissue damage and progression of COVID‐19. Induction of these potentially detrimental T‐cell responses should be considered when developing and implementing effective COVID‐19 control strategies.

Objectives: Disease‐modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG₃ antibodies and their uncharacterised B‐cell clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG₃⁺ B cells involved in MS progression could improve diagnosis, could inform timely disease intervention and may lead to new DMTs that target B cells more specifically.Methods: We designed a 31‐parameter B‐cell‐focused mass cytometry panel to interrogate the role of peripheral blood IgG₃⁺ B cells in MS progression of two different patient cohorts: one to investigate the B‐cell subsets involved in conversion from clinically isolated syndrome (CIS) to MS; and another to compare MS patients with inactive or active stages of disease. Each independent cohort included a group of non‐MS controls.Results: Nine distinct CD20⁺IgD⁻IgG₃⁺ B‐cell subsets were identified. Significant changes in the proportion of CD21⁺CD24⁺CD27⁻CD38⁻ and CD27⁺CD38^hiCD71^hi memory B‐cell subsets correlated with changes in serum IgG₃ levels and time to conversion from CIS to MS. The same CD38⁻ double‐negative B‐cell subset was significantly elevated in MS patients with active forms of the disease. A third CD21⁺CD24⁺CD27⁺CD38⁻ subset was elevated in patients with active MS, whilst narrowband UVB significantly reduced the proportion of this switched‐memory B‐cell subset.Conclusion: We have identified previously uncharacterised subsets of IgG₃⁺ B cells and shown them to correlate with autoimmune attacks on the central nervous system (CNS). These results highlight the potential for therapies that specifically target IgG₃⁺ B cells to impact MS progression.

B cells play a major role in multiple sclerosis (MS), with many successful therapeutics capable of removing them from circulation. One such therapy, alemtuzumab, is thought to reset the immune system without the need for ongoing therapy in a proportion of patients. The exact cells contributing to disease pathogenesis and quiescence remain to be identified. We utilized mass cytometry to analyze B cells from the blood of patients with relapse‐remitting MS (RRMS) before and after alemtuzumab treatment, and during relapse. A complementary RRMS cohort was analyzed by single‐cell RNA sequencing. The R package “Spectre” was used to analyze these data, incorporating FlowSOM clustering, sparse partial least squares‐discriminant analysis and permutational multivariate analysis of variance. Immunoglobulin (Ig)A⁺ and IgG₁⁺ B‐cell numbers were altered, including higher IgG₁⁺ B cells during relapse. B‐cell linker protein (BLNK), CD40 and CD210 expression by B cells was lower in patients with RRMS compared with non‐MS controls, with similar results at the transcriptomic level. Finally, alemtuzumab restored BLNK, CD40 and CD210 expression by IgA⁺ and IgG₁⁺ B cells, which was altered again during relapse. These data suggest that impairment of IgA⁺ and IgG₁⁺ B cells may contribute to MS pathogenesis, which can be restored by alemtuzumab.

Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti–CTLA-4 and anti–PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared with patients who did not develop colitis, and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8 ⁺ T cells and Th1 CD4 ⁺ T cells in patients who developed colitis. Our data also suggest that CD8 ⁺ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together, our data show that exaggerated innate and T cell responses to combination immunotherapy synergize to propel colitis in susceptible patients.