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Abstract Background With the ongoing prevalence of the emerging variant and global vaccination efforts, the optimal surgical timing for patients with resectable lung cancer in the Omicron-dominant period requires further investigation. Methods This prospective multicenter study involved patients who underwent radical surgery for lung cancer between January 29, 2023 and March 31, 2023. Patients were categorized into four groups based on the interval between SARS-CoV-2 infection and surgery. The main outcomes evaluated were 30-day mortality and 30-day morbidity. Results A total of 2081 patients were enrolled in the study, of which 1837 patients (88.3%) had a confirmed SARS-CoV-2 diagnosis before surgery. Notably, no instances of 30-day mortality were observed in any patient. Patients without prior infection had a 30-day morbidity rate of 15.2%, with postoperative pneumonia occurring in 7.0% of cases. In contrast, patients diagnosed with SARS-CoV-2 before surgery had significantly higher rates of 30-day morbidity and postoperative pneumonia when surgery was performed within 4–5 weeks (adjusted odds ratio (aOR) (95% CI):2.18 (1.29–3.71) and 2.39 (1.21–4.79), respectively) or within 6–7 weeks (aOR (95% CI):2.07 (1.36–3.20) and 2.10 (1.20–3.85), respectively). Conversely, surgeries performed ≥ 8 weeks after SARS-CoV-2 diagnosis exhibited similar risks of 30-day morbidity and pneumonia compared to those in the no prior infection group (aOR (95% CI):1.13 (0.77–1.70) and 1.12 (0.67–1.99), respectively). Conclusions Thoracic surgery for lung cancer conducted 4–7 weeks after SARS-CoV-2 infection is still associated with an increased risk of 30-day morbidity in the Omicron-dominant period. Therefore, surgeons should carefully assess the individual risks and benefits to formulate an optimal surgical strategy for patients with lung cancer with a history of SARS-CoV-2 infection.

Abstract This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II–III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2–4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3–48.1) in arm A and were 55.6% (95% CI 21.2–86.3) and 11.1% (95% CI 0.3–48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8–61.6) and 55.6% (95% CI 21.2–86.3). With a median follow-up of 22.4 months (95% CI 19.0–26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II–III NSCLC.

Abstract Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Abstract Background Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. Methods We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). Results Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. Conclusions Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

Abstract Background This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II–III non-small-cell lung cancer (NSCLC). Methods Patient eligibility mainly involved treatment-naive, clinical stage II–III and wild-type EGFR/ALK NSCLC. The patients received 2–4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. Results In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). Conclusions Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II–III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. Trial registration ChiCTR1900024014, June 22, 2019.

Abstract Background The diversity of histologic composition reflects the inter- and intra-tumor heterogeneity of lung adenocarcinomas (LUADs) macroscopically. Insights into the oncological characteristics and tumor microenvironment (TME) of different histologic subtypes of LUAD at the single-cell level can help identify potential therapeutic vulnerabilities and combinational approaches to improve the survival of LUAD patients. Methods Through comparative profiling of cell communities defined by scRNA-seq data, we characterized the TME of LUAD samples of distinct histologic subtypes, with relevant results further confirmed in multiple bulk transcriptomic, proteomic datasets and an independent immunohistochemical validation cohort. Results We find that the hypoxic and acidic situation is the worst in the TME of solid LUADs compared to other histologic subtypes. Besides, the tumor metabolic preferences vary across histologic subtypes and may correspondingly impinge on the metabolism and function of immune cells. Remarkably, tumor cells from solid LUADs upregulate energy and substance metabolic activities, particularly the folate-mediated one-carbon metabolism and the key gene MTHFD2, which could serve as a potential therapeutic target. Additionally, ubiquitination modifications may also be involved in the progression of histologic patterns. Immunologically, solid LUADs are characterized by a predominance of exhausted T cells and immunosuppressive myeloid cells, where the hypoxic, acidified and nutrient-deprived TME has a non-negligible impact. Discrepancies in stromal cell function, evidenced by varying degrees of stromal remodeling and fibrosis, may also contribute to the specific immune phenotype of solid LUADs. Conclusions Overall, our research proposes several potential entry points to improve the immunosuppressive TME of solid LUADs, thereby synergistically potentiating their immunotherapeutic efficacy, and may provide precise therapeutic strategies for LUAD patients of distinct histologic subtype constitution.

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could provide survival benefits for locally advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). However, the role of radical surgery for EGFR-TKI treated stage IIIB EGFRm NSCLC remains controversial. This study attempted to assess the feasibility of neoadjuvant EGFR-TKI followed by radical surgery for stage IIIB EGFRm NSCLC.Patients and MethodsBetween 2013 and 2020, EGFRm lung adenocarcinoma (LUAD) patients in clinical stage IIIB undergoing neoadjuvant EGFR-TKI followed by surgery (T-S-Arm) and EGFR-TKI alone (T-Arm) were reviewed retrospectively in Shanghai Pulmonary Hospital (SPH). The chi-square test, Student’s t-test or Fisher’s exact test was performed for analysis of baseline characteristics. Progression-free survival (PFS) was estimated using the Kaplan-Meier analysis. Multivariate Cox regression analysis was used to identify independent predictors of progression.ResultsA total of 43 patients were divided into T-S-Arm (n = 21) and T-Arm (n = 22). Patients were well-balanced between the two arms. The majority of patients were female (n = 25, 58.1%), non-smokers (n = 35, 81.4%), first-generation of EGFR-TKI treatment (n = 39, 90.7%), and exon 19 deletions (19-DEL) (n = 26, 60.5%). The median diagnostic age was 63.0 years [interquartile range (IQR), 54.0-67.5 years). At the cut-off date with June 30th 2022, median follow-up time was 28 months (IQR, 20-39 months). Neoadjuvant EGFR-TKI treatment followed by radical surgery could significantly improve the median PFS compared with patients underwent EGFR-TKI alone (23.0 months vs 14.5 months, P = 0.002). Multivariate Cox regression analysis demonstrated that radical surgery (T-S-Arm vs. T-Arm, HR: 0.406; 95% CI: 0.207-0.793, P = 0.027) was the only independent predictor for disease progression. The stratified analysis demonstrated patients with N2 disease could benefit from radical surgery (HR, 0.258; 95% CI, 0.107-0.618), especially for patients harboring L858R mutation (HR, 0.188; 95% CI, 0.059-0.604).ConclusionsFor stage IIIB EGFRm NSCLC patients, the prognosis might be improved by neoadjuvant EGFR-TKI followed by radical surgery versus EGFR-TKI alone, especially for those with N2 disease and harboring L858R mutation.

Abstract Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy with high metastasis. However, the heterogeneity of metastatic SCLC at the single‐cell level remains elusive. The single‐cell transcriptome of a total of 24 081 cells in metastatic lymph node samples from seven SCLC patients via endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) is examined. Genomic alterations are also examined by whole exome sequencing (WES) and the immune infiltration between SCLC and non‐SCLC (NSCLC) is compared using public single‐cell RNA sequencing (scRNA‐seq) data. It is identified that malignant cells in lymph‐node metastatic SCLC have inter‐patient and intra‐tumor heterogeneity characterized by distinct ASCL1 and NEUROD1 expression patterns. High expression of genes such as FZD8 in WNT pathway is associated with drug resistance in malignant cells. Compared to NSCLC, SCLC harbors a unique immunosuppressive tumor microenvironment. Malignant cells exhibit a pattern of attenuated MHC‐I antigen presentation‐related gene expression, which is associated with relatively low proportion of exhausted T cells. Natural killer (NK) cells display impaired antitumor function with high expression of TGFBR2. This work characterizes the inter‐patient and intra‐tumor heterogeneity of metastatic SCLC and uncovers the exhaustion signatures in NK cells, which may pave the way for novel treatments for SCLC including immune checkpoint blockade‐based immunotherapy.

Summary: Knowledge of the tumor microenvironment (TME) in patients with early lung cancer, especially in comparison with the matched adjacent tissues, remains lacking. To characterize TME of early-stage lung adenocarcinoma, we performed RNA-seq profiling on 58 pairs of minimally invasive adenocarcinoma (MIA) tumors and matched adjacent normal tissues. MIA tumors exhibited an adaptive TME characterized by high CD4+ T cell infiltration, high B-cell activation, and low CD8+ T cell infiltration. The high expression of markers for B cells, activated CD4+ T cells, and follicular helper T (Tfh) cells in bulk MIA samples and three independent single-cell RNA-seq datasets implied tertiary lymphoid structures (TLS) formation. Multiplex immunohistochemistry staining validated TLS formation and revealed an enrichment of follicular regulatory T cells (Tfr) in TLS follicles, which may explain the lower CD8+ T cell infiltration and attenuated anti-tumor immunity in MIA. Our study demonstrates how integrating transcriptome and pathology characterize TME and elucidate potential mechanisms of tumor immune evasion.