Cancer patients are highly vulnerable to SARS-CoV-2 infections due to frequent contacts with the healthcare system, immunocompromised state from cancer or its therapies, supportive medications such as steroids and most importantly their advanced age and comorbidities. Patients with lung cancer have consistently been reported to suffer from an increased risk of death compared with other cancers. This is possibly due to the combination of specific pathophysiological aspects, including underlying pulmonary compromise due to smoking history and the increased specific pressures on respiratory healthcare services caused by the related pandemic. Rationally and safely treating patients with lung cancer during the pandemic has become a continuous challenge over the last year. Deciding whether to offer, modify, postpone or even cancel treatments for this particular patient’s population has become the crucial recurrent dilemma for lung cancer professionals. Chemotherapy, immunotherapy and targeted agents represent distinct risks factors in the context of COVID-19 that should be balanced with the short-term and long-term consequences of delaying cancer care. Despite the rapid and persistent trend of the pandemic, declared by WHO on March 11, 2020, and still ongoing at the time of writing (January 2021), various efforts were made by oncologists worldwide to understand the impact of COVID-19 on patients with cancer. Adapted recommendations of our evidence-based practice guidelines have been developed for all stakeholders. Different small and large-scale registries, such as the COVID-19 and Cancer Consortium (CCC19) and Thoracic Cancers International COVID-19 Collaboration quickly collected data, supporting cancer care decisions under the challenging circumstance created by the COVID-19 pandemic. Several recommendations were developed as guidance for prioritizing the various aspects of lung cancer care in order to mitigate the adverse effects of the COVID-19 healthcare crisis, potentially reducing the morbidity and mortality of our patients from COVID-19 and from cancer. These recommendations helped inform decisions about treatment of established disease, continuation of clinical research and lung cancer screening. In this review, we summarize available evidence regarding the direct and indirect impact of the COVID-19 pandemic on lung cancer care and patients.

The majority of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (R/M) do not benefit from anti-PD-1 therapy. Hypoxia induced immunosuppression may be a barrier to immunotherapy. Therefore, we examined the metabolic effect of anti-PD-1 therapy in a murine MEER HNSCC model as well as intratumoral hypoxia in R/M patients. In order to characterize the tumor microenvironment in PD-1 resistance, a MEER cell line was created from the parental line that are completely resistant to anti-PD-1. These cell lines were then metabolically profiled using seahorse technology and injected into C57/BL6 mice. After tumor growth, mice were pulsed with pimonidazole and immunofluorescent imaging was performed to analyze hypoxia and T cell infiltration. To validate the preclinical results, we analyzed tissues from R/M patients (n=36) treated with anti-PD-1 mAb, via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs and the percent area (CAIX) and mean intensity (I) of carbonic anhydrase IX in tumor. We analyzed disease control rate (DCR), progression free survival (PFS), and overall survival (OS) using proportional odds and proportional hazards (Cox) regression. We found that anti-PD-1 resistant MEER has significantly higher oxidative metabolism, while there was no difference in glycolytic metabolism. Intratumoral hypoxia was significantly increased and CD8+ T cells decreased in anti-PD-1 resistant tumors compared with parental tumors in the same mouse. In R/M patients, lower tumor hypoxia by CAIX/I was significantly associated with DCR (p=0.007), PFS, and OS, and independently associated with response (p=0.028) and PFS (p=0.04) in a multivariate model including other significant immune factors. During PD-1 resistance, tumor cells developed increased oxidative metabolism leading to increased intratumoral hypoxia and a decrease in CD8+ T cells. Lower tumor hypoxia was independently associated with increased efficacy of anti-PD-1 therapy in patients with R/M HNSCC. To our knowledge this is the first analysis of the effect of hypoxia in this patient population and highlights its importance not only as a predictive biomarker but also as a potential target for therapeutic intervention.

One of the mechanisms by which advanced prostate cancer develops resistance to androgen deprivation therapy is the elevated expression of C-terminally truncated androgen receptor (AR) variants. These variants, such as AR-V7, originate from aberrant splicing of the AR pre-mRNA and the inclusion of a cryptic exon containing a premature stop codon in the mRNA. The resulting loss of the ligand-binding domain allows AR-V7 to act as a constitutively active transcription factor. Here, we designed two antisense oligonucleotides (AONs) directed against cryptic splicing signals within the AR pre-mRNA. These two AONs, AON-ISE and AON-ESE, demonstrated high efficiency in silencing AR-V7 splicing without affecting full-length AR expression. The subsequent downregulation of AR-V7-target gene UBE2C was accompanied by inhibition of androgen-independent cell proliferation and induction of apoptosis in castration-resistant prostate cancer (CRPC)-derived cell line models 22Rv1, DuCaP, and VCaP. Our results show that splicing-directed AONs can efficiently prevent expression of AR-V7, providing an attractive new therapeutic option for the treatment of CRPC.

Microfold (M) cells reside in the intestinal epithelium of Peyer's patches (PP). Their unique ability to take up and transport antigens from the intestinal lumen to the underlying lymphoid tissue is key in the regulation of the gut-associated immune response. Here, we applied a multi-omics approach to investigate the molecular mechanisms that drive M cell differentiation in mouse small intestinal organoids. We generated a comprehensive profile of chromatin accessibility changes and transcription factor dynamics during in vitro M cell differentiation, allowing us to uncover numerous cell type-specific regulatory elements and associated transcription factors. By using single-cell RNA sequencing, we identified an enterocyte and M cell precursor population. We used our newly developed computational tool SCEPIA to link precursor cell-specific gene expression to transcription factor motif activity in cis-regulatory elements, uncovering high expression of and motif activity for the transcription factor ONECUT2. Subsequent in vitro and in vivo perturbation experiments revealed that ONECUT2 acts downstream of the RANK/RANKL signalling axis to support enterocyte differentiation, thereby restricting M cell lineage specification. This study sheds new light on the mechanism regulating cell fate balance in the PP, and it provides a powerful blueprint for investigation of cell fate switches in the intestinal epithelium.