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Pulmonary large cell neuroendocrine carcinoma is an aggressive subtype of lung cancer. Here, the authors identify distinct subtypes based on genomic alterations and transcriptomic alterations.

Exploratory post hoc analysis of molecular residual disease from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated stage IB–IIIA non-small-cell lung cancer shows that molecular residual disease detection predicts disease recurrence with long-term adjuvant osimertinib treatment.

Clinical and correlative biomarker results from a phase 1 clinical trial in patients with different solid tumours are presented; the findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A (anti-PD-L1).

Prospective assessment of a T-cell-inflamed gene signature and tumor mutational burden is feasible in patients with non-small cell lung cancer randomized to receive various anti-PD-1-based treatment combinations, with an encouraging objective response rate for first-line pembrolizumab + lenvatinib in one biomarker-defined group.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

The HARMONi-2 trial demonstrated a significant improvement in progression-free survival with ivonescimab, a bispecific PD-1×VEGF antibody, versus pembrolizumab in patients with PD-L1-positive advanced-stage non-small-cell lung cancer. Ivonescimab might enhance antitumour immunity by normalizing the tumour vasculature and reversing immunosuppression. Although promising, global applicability of ivonescimab awaits further validation, including overall survival results, in diverse populations.

A molecule has now been characterized that acts to inhibit a cancer-causing form of KRAS protein and stimulate the immune system. The inhibitor is one of the first of its kind to show anticancer activity in the clinic.

Genomic and transcriptomic analysis of 393 non-small cell lung cancer patients treated with checkpoint inhibitors identifies molecular features associated with response.

Terpene cyclases catalyze the formation of diverse hydrocarbon scaffolds found in terpenoids. Here, the authors report the cryptic function of class I terpene cyclases as aromatic prenyltransferases and the universality of this cryptic feature is confirmed using enzymes from different sources.

Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.

A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.

Classifiers trained on a large microarray gene expression dataset can assess pluripotency in query samples of human cells.

Many clinical trials of targeted therapies have produced disappointing results, indicating that many challenges must be addressed to advance this field. The authors discuss the importance of novel statistical designs, the need for biopsy sampling in clinical trials and appropriate biomarker identification for improving treatment outcomes.

Blockade of sialic acid-binding protein Siglec-15 expressed in cancer and tumor-infiltrating myeloid cells reverses immunesupression and represents a novel target for cancer immunotherapy independent from the PD-1/PD-L1 axis.

A high tumour mutational burden (≥10 mutations per megabase) is a companion biomarker in the histology-agnostic approval of pembrolizumab for treatment-refractory advanced-stage solid tumours, and continues to be an exploratory predictive biomarker for immune-checkpoint inhibitors in non-small-cell lung cancer. Herein, we discuss recent results from the first phase III trial evaluating blood-based tumour mutational burden in patients with treatment-naive advanced-stage non-small-cell lung cancer.

Patients with stage III non-small-cell lung cancer (NSCLC) comprise a heterogeneous population; the role of surgical resection in this setting has been controversial. Albain and colleagues recently demonstrated that trimodality therapy with lobectomy had clinical benefit for patients with pathologic nodal N2 stage III NSCLC. We discuss the trial and its implications for future lung cancer therapy.

Targeting Siglec-15 may be an effective alternative therapy for patients that do not respond to PD-1/PD-L1 inhibition. In this study, the authors show broad expression of this potential immune modulatory target in a wide range of cancer types. These data may inform future clinical development and show potential for future companion diagnostic tests for Siglec-15 therapeutics.

Disease signatures in high-dimensional biomedical data are detected with a visualization algorithm.

The CHECKMATE-227 trial of nivolumab and ipilimumab presents a potential new frontline chemotherapy-sparing treatment option for patients with PD-L1-positive non-small-cell lung cancer and perhaps, in the future, also for those with PD-L1-negative disease. Indeed, the true predictive value of PD-L1 as well as tumour mutational burden remains to be determined, as neither biomarker segregates clearly with responsiveness.

This Perspective discusses recent developments in NSCLC immunotherapy and targeted therapy, and highlights the key challenges and future directions for NSCLC management.

Daniel Powell et al. present a high-quality genome assembly of the Eurasian spruce bark beetle, Ips typographus, which is known to cause substantial damage to European forests. Their results provide an important resource for investigation of the underlying physiology of this pest species and limit future threats to European forests.

Organotypic three-dimensional (3D) cell culture models are becoming more widely used in infectious-disease research, as they mimic the 3D architecture ofin vivotissues more faithfully than traditional 2D cell culture. Cheryl Nickerson and colleagues review one such 3D model system, the rotating wall vessel bioreactor, and its applications in the study of microbial pathogenesis and host–pathogen interactions.

This Perspective article discusses the mechanisms used by tumours to evade the immune system, collectively called adaptive immune resistance (AIR), and why defining AIR mechanisms in the tumour microenvironment is key in immunotherapy development.

Siglec-15 is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. The aim of this study was to develop an immunohistochemical assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, the authors created and validated an assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. This study may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.

Immune-checkpoint inhibitors (ICIs) are now standard-of-care therapies for patients with advanced-stage non-small-cell lung cancer (NSCLC) without a targetable driver alteration. Various ICIs or combination regimens have been approved in this setting, relative to chemotherapy, although no prospective data are available comparing the various ICI-based approaches. Here, the authors provide guidance on selecting the optimal ICI-based therapy and highlight several future research directions that will probably further improve the outcomes of patients with advanced-stage NSCLC.

Using a high throughput, random bacterial peptide display approach applied to patient serum samples, Haynes, Kamath, Bozekowski et al identify the antigens and epitopes that elicit a SARS-CoV-2 humoral response. They identify differences depending on disease severity and further in silico analysis suggests decreased epitope signal for Q677P but not for D614G mutant SARSCoV-2 strains.