Integrated single-cell transcriptomic and BCR analyses reveal how antibody class switching influences human B cell fate and function.

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate-limiting enzyme in this pathway, led to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis was a characteristic of germinal center B cell–derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induced apoptosis in lymphoma cells, reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.

The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift in the treatment of chronic lymphocytic leukaemia (CLL) over the last decade. Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some of which are due to the off-target inhibition of kinases other than BTK. As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials. Despite the increased specificity for BTK, side effects and treatment resistance remain therapeutic challenges. As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib. The alternative mechanisms of BTK-binding of these agents has the potential to overcome resistance mutations, something that has been borne out in early clinical trial data. A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases.

The coronavirus disease 2019 (COVID-19) pandemic has caused considerable global disruption to clinical practice. This article will review the impact that the pandemic has had on oncology clinical trials. It will assess the effect of the COVID-19 situation on the initial presentation and investigation of patients with suspected cancer. It will also review the impact of the pandemic on the subsequent management of cancer patients, and how clinical trial approval, recruitment, and conduct were affected during the pandemic. An intriguing aspect of the pandemic is that clinical trials investigating treatments for COVID-19 and vaccinations against the causative virus, SARS-CoV-2, have been approved and conducted at an unprecedented speed. In light of this, this review will also discuss the potential that this enhanced regulatory environment could have on the running of oncology clinical trials in the future.

Breath analysis is a promising non-invasive method for the detection and management of lung cancer. Exhaled breath contains a complex mixture of volatile and non-volatile organic compounds that are produced as end-products of metabolism. Several studies have explored the patterns of these compounds and have postulated that a unique breath signature is emitted in the setting of lung cancer. Most studies have evaluated the use of gas chromatography and mass spectrometry to identify these unique breath signatures. With recent advances in the field of analytical chemistry and machine learning gaseous chemical sensing and identification devices have also been created to detect patterns of odorant molecules such as volatile organic compounds. These devices offer hope for a point-of-care test in the future. Several prospective studies have also explored the presence of specific genomic aberrations in the exhaled breath of patients with lung cancer as an alternative method for molecular analysis. Despite its potential, the use of breath analysis has largely been limited to translational research due to methodological issues, the lack of standardization or validation and the paucity of large multi-center studies. It is clear however that it offers a potentially non-invasive alternative to investigations such as tumor biopsy and blood sampling.