Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Timeliness of surgery for early-stage lung cancer: Patient factors and predictors.

Objectives: Time-to-treatment initiation is an important consideration for patients undergoing thoracic surgery for early-stage lung cancer because delays have the potential to adversely affect outcomes. This study seeks to quantify time-to-treatment initiation for patients with clinical stage I lung cancer, explore patient factors and predictors that lead to an increased time-to-treatment initiation, and compare surgeon perception of appropriate time-to-treatment initiation to the results. Methods: Time-to-treatment initiation was determined for patients enrolled in the Mount Sinai Initiative for Early Lung Cancer Research on Treatment study who underwent surgical resection for clinical stage I lung cancer between March 2016 and December 2021. The following dates were determined: (1) date of first suspicious radiologic imaging, (2) date of first biopsy, and (3) date of surgery. A total of 15 thoracic surgeons who participated in the Mount Sinai Initiative for Early Lung Cancer Research on Treatment were assessed on their perception on time-to-treatment initiation. Results: For 638 patients, median time from first suspicious imaging findings to biopsy was 40 days, biopsy to surgery was 37 days, and suspicious imaging to surgery was 84 days. Significant factors that resulted in longer time-to-treatment initiation in the multivariate analysis were African American or Black race (P = .005), vascular disease (P = .01), and median household income less than $75,000 (P = .04). Although the surgeon's perception was that the average time from biopsy to surgery was 28 days, it was longer for 63.5% of participants; surgeon perception of maximum time between diagnosis and surgery was 84 days and longer for 28.7% of participants. Conclusions: Patient factors such as race, income, and comorbidities were found to have differences in time-to-treatment initiation. Delays to surgery exceeded the expectations of thoracic surgeons.

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

Should Treatment of Mesothelioma Include Surgery? MARS2 Fails to Land.

The presentation of the Mesothelioma and Radical Surgery 2 trial, a randomized controlled trial comparing pleurectomy/decortication to no surgery, injected new data into the contentious discussion surrounding the use of surgery in the management of diffuse pleural mesothelioma. We review the trial results in the context of the existing work surrounding the use of surgery in pleural mesothelioma.

The value of high-risk clinicopathologic features for chemotherapy in stage I non-small cell lung cancer: a propensity score-matched study.

Background: Surgical resection is the main treatment for early-stage non-small cell lung cancer (NSCLC), but recurrence remains a concern. Adjuvant chemotherapy has been shown to have survival benefits for resected stage II and III NSCLC, but debate continues regarding its use in stage I NSCLC. High-risk features, such as tumor size and stage, are considered in deciding whether to administer adjuvant chemotherapy. Methods: The data of 666,689 patients diagnosed with lung cancer from 2004 to 2016 were collected from the Surveillance, Epidemiology, and End Results database. Ultimately, 26,160 patients diagnosed with stage I NSCLC were included in the study based on a screening procedure. Results: After matching, 4,285 patients were identified, of whom 1,440 (33.6%) received chemotherapy. High-risk clinicopathologic features, including a high histologic grade, visceral pleural invasion (VPI), the examination of an insufficient number of lymph nodes (LNs), and limited resection, were independent risk factors for a poor prognosis. Chemotherapy significantly improved lung cancer-specific survival (LCSS) and overall survival (OS) in stage I patients with VPI [LCSS: hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.706-0.998, P=0.047; OS: HR: 0.711, 95% CI: 0.612-0.826, P<0.001], regardless of whether or not the patient had fewer than 11 LNs (LCSS: HR: 0.809, 95% CI: 0.664-0.986, P=0.04; OS: HR: 0.677, 95% CI: 0.570-0.803, P<0.001). Chemotherapy was only observed to improve OS for stage IB patients with a high histologic grade when combined with either or both of the following high-risk factors: the presence of VPI and fewer than 11 LNs examined. Conclusions: The presence of VPI was the dominant predictor and the examination of an insufficient number of LNs was the secondary indicator, and a high histologic grade was a potential indicator of the need to administer chemotherapy in the treatment of stage I NSCLC.

Change in quality of life of stage IA non-small cell lung cancer after surgery or radiation therapy.

Background: Few studies have examined the differential impact of stereotactic body radiotherapy (SBRT) and surgery for early-stage non-small cell lung cancer (NSCLC) on quality of life (QoL) during the first post-treatment year. Methods: A prospective cohort of stage IA NSCLC patients undergoing surgery or SBRT at Mount Sinai Health System had QoL measured before treatment, and 2, 6, and 12 months post-treatment using: 12-item Short Form Health Survey version 2 (SF-12v2) [physical component summary (PCS) and mental component summary (MCS)], Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS), and the Patient Health Questionnaire-4 (PHQ-4) measuring depression and anxiety. Locally weighted scatterplot smoothing (LOWESS) was fitted to identify the best interval knot for the change in the QoL trends post-treatment, adjusted piecewise linear mixed effects model was developed to estimate differences in baseline, 2- and 12-month scores, and rates of change. Results: In total, 503 (88.6%) patients received surgery and 65 (11.4%) SBRT. LOWESS plots suggested QoL changed at 2 months post-surgery. Worsening in PCS was observed for both surgery and SBRT within 2 months after treatment but was only significant for surgical patients (-2.11, P<0.001). Two months later, improvements were observed for surgical but not SBRT patients (0.63 vs. -0.30, P<0.001). Surgical patients had significantly better PCS (P<0.001) and FACT-LCS (P<0.001) scores 1-year post-treatment compared to baseline, but not SBRT patients. Both surgical and SBRT patients reported significantly less anxiety 1-year post-treatment compared to baseline (P<0.001 and P=0.03). Decrease in depression from baseline to 1-year post-treatment was only significant for surgical patients (P<0.001). Conclusions: Post-treatment, surgical patients exhibited improvements in physical health and reductions in lung cancer symptoms following initial deterioration within the first two months; in contrast, SBRT patients showed persistent decline in these areas throughout the year. Nonetheless, improved mental health was noted across both patient categories post-treatment. Targeted interventions and continuous monitoring are recommended during the initial 2 months post-surgery and throughout the year post-SBRT to alleviate physical and mental distress in patients.