Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

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B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Environmental carcinogenic exposures are major contributors to global disease burden yet how they promote cancer is unclear. Over 70 years ago, the concept of tumour promoting agents driving latent clones to expand was rst proposed. In support of this model, recent evidence suggests that human tissue contains a patchwork of mutant clones, some of which harbour oncogenic mutations, and many environmental carcinogens lack a clear mutational signature. We hypothesised that the environmental carcinogen, <2.5μm particulate matter (PM2.5), might promote lung cancer promotion through nonmutagenic mechanisms by acting on pre-existing mutant clones within normal tissues in patients with lung cancer who have never smoked, a disease with a high frequency of EGFR activating mutations. We analysed PM2.5 levels and cancer incidence reported by UK Biobank, Public Health England, Taiwan Chang Gung Memorial Hospital (CGMH) and Korean Samsung Medical Centre (SMC) from a total of 463,679 individuals between 2006-2018. We report associations between PM2.5 levels and the incidence of several cancers, including EGFR mutant lung cancer. We nd that pollution on a background of EGFR mutant lung epithelium promotes a progenitor-like cell state and demonstrate that PM accelerates lung cancer progression in EGFR and Kras mutant mouse lung cancer models. Through parallel exposure studies in mouse and human participants, we nd evidence that in ammatory mediators, such as interleukin-1 , may act upon EGFR mutant clones to drive expansion of progenitor cells. Ultradeep mutational pro ling of histologically normal lung tissue from 247 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 33% of normal tissue samples, respectively. These results support a tumour-promoting role for PM acting on latent mutant clones in normal lung tissue and add to evidence providing an urgent mandate to address air pollution in urban areas.

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.