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Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0–5%, >5–30%, >30–80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 . Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease with high mortality and is refractory to treatment. Pulmonary macrophages can both promote and repress fibrosis, however molecular mechanisms regulating macrophage functions during fibrosis remain poorly understood. FOXM1 is a transcription factor and is not expressed in quiescent lungs. Herein, we show that FOXM1 is highly expressed in pulmonary macrophages within fibrotic lungs of IPF patients and mouse fibrotic lungs. Macrophage-specific deletion of Foxm1 in mice (myFoxm1-/-) exacerbated pulmonary fibrosis. Inactivation of FOXM1 in vivo and in vitro increased p38 MAPK signaling in macrophages and decreased DUSP1, a negative regulator of p38 MAPK pathway. FOXM1 directly activated Dusp1 promoter. Overexpression of DUSP1 in FOXM1-deficient macrophages prevented activation of p38 MAPK pathway. Adoptive transfer of wild-type monocytes to myFoxm1-/- mice alleviated bleomycin-induced fibrosis. Altogether, contrary to known pro-fibrotic activities in lung epithelium and fibroblasts, FOXM1 has anti-fibrotic function in macrophages by regulating p38 MAPK.

Alveolar epithelial cells (AECs) participate in the pathogenesis of pulmonary fibrosis, producing pro‐inflammatory mediators and undergoing epithelial‐to‐mesenchymal transition (EMT). Herein, we demonstrated the critical role of Forkhead Box M1 (Foxm1) transcription factor in radiation‐induced pulmonary fibrosis. Foxm1 was induced in AECs following lung irradiation. Transgenic expression of an activated Foxm1 transcript in AECs enhanced radiation‐induced pneumonitis and pulmonary fibrosis, and increased the expression of IL‐1 β, Ccl2 , Cxcl5 , Snail1 , Zeb1 , Zeb2 and Foxf1 . Conditional deletion of Foxm1 from respiratory epithelial cells decreased radiation‐induced pulmonary fibrosis and prevented the increase in EMT‐associated gene expression. siRNA‐mediated inhibition of Foxm1 prevented TGF‐β‐induced EMT in vitro . Foxm1 bound to and increased promoter activity of the Snail1 gene, a critical transcriptional regulator of EMT. Expression of Snail1 restored TGF‐β‐induced loss of E‐cadherin in Foxm1‐deficient cells in vitro . Lineage‐tracing studies demonstrated that Foxm1 increased EMT during radiation‐induced pulmonary fibrosis in vivo . Foxm1 is required for radiation‐induced pulmonary fibrosis by enhancing the expression of genes critical for lung inflammation and EMT. This study establishes the in vivo relevance of FoxM1 in the context of radiation‐induced fibrosis. FoxM1 ablation in the respiratory epithelium supports a regulatory role during EMT and pulmonary inflammation that could become of therapeutic relevance.

Lung cancer remains one of the most prominent public health challenges, accounting for the highest incidence and mortality among all human cancers. While pulmonary invasive mucinous adenocarcinoma (PIMA) is one of the most aggressive types of non-small cell lung cancer, transcriptional drivers of PIMA remain poorly understood. In the present study, we found that Forkhead box M1 transcription factor (FOXM1) is highly expressed in human PIMAs and associated with increased extracellular mucin deposition and the loss of NKX2.1. To examine consequences of FOXM1 expression in tumor cells in vivo, we employed an inducible, transgenic mouse model to express an activated FOXM1 transcript in urethane-induced benign lung adenomas. FOXM1 accelerated tumor growth, induced progression from benign adenomas to invasive, metastatic adenocarcinomas, and induced SOX2, a marker of poorly differentiated tumor cells. Adenocarcinomas in FOXM1 transgenic mice expressed increased MUC5B and MUC5AC, and reduced NKX2.1, which are characteristics of mucinous adenocarcinomas. Expression of FOXM1 in KrasG12D transgenic mice increased the mucinous phenotype in KrasG12D-driven lung tumors. Anterior Gradient 2 (AGR2), an oncogene critical for intracellular processing and packaging of mucins, was increased in mouse and human PIMAs and was associated with FOXM1. FOXM1 directly bound to and transcriptionally activated human AGR2 gene promoter via the -257/-247 bp region. Finally, using orthotopic xenografts we demonstrated that inhibition of either FOXM1 or AGR2 in human PIMAs inhibited mucinous characteristics, and reduced tumor growth and invasion. Altogether, FOXM1 is necessary and sufficient to induce mucinous phenotypes in lung tumor cells in vivo.

Despite known histological, biological, and clinical differences between lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), relatively little is known about the spatial differences in their corresponding immune contextures. Our study of over 1000 LUAD and LUSC tumors revealed that computationally derived patterns of tumor-infiltrating lymphocytes (TILs) on H&E images were different between LUAD ( N  = 421) and LUSC ( N  = 438), with TIL density being prognostic of overall survival in LUAD and spatial arrangement being more prognostically relevant in LUSC. In addition, the LUAD-specific TIL signature was associated with OS in an external validation set of 100 NSCLC treated with more than six different neoadjuvant chemotherapy regimens, and predictive of response to therapy in the clinical trial CA209-057 ( n  = 303). In LUAD, the prognostic TIL signature was primarily comprised of CD4 + T and CD8 + T cells, whereas in LUSC, the immune patterns were comprised of CD4 + T, CD8 + T, and CD20 + B cells. In both subtypes, prognostic TIL features were associated with transcriptomics-derived immune scores and biological pathways implicated in immune recognition, response, and evasion. Our results suggest the need for histologic subtype-specific TIL-based models for stratifying survival risk and predicting response to therapy. Our findings suggest that predictive models for response to therapy will need to account for the unique morphologic and molecular immune patterns as a function of histologic subtype of NSCLC.

PurposeCheckMate 915 (NCT03068455) compared adjuvant nivolumab monotherapy versus combination nivolumab+ipilimumab in patients with resected stage III/IV melanoma. This exploratory analysis was performed to identify biomarkers that correlate with benefit from adjuvant immunotherapy.Patients and methods1,844 patients received nivolumab 480 mg every 4 weeks or nivolumab 240 mg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks. Tumor and peripheral biomarkers were evaluated, including tumor-informed circulating tumor DNA (ctDNA) at postresection baseline and on-treatment, for their association with recurrence-free survival and distant metastases-free survival.ResultsBiomarker analyses were conducted in 60–96% of the intention-to-treat population. ctDNA positivity at baseline (seen in 16.2% of patients) and on-treatment was associated with higher risk of recurrence than ctDNA negativity (HR, 1.97; 95% CI, 1.57 to 2.46), with a high specificity (87%) and modest sensitivity (39%). ctDNA status, tumor mutational burden (TMB) status (TMB < or ≥350 mutations/tumor) and interferon gamma-RNA signature score (< or ≥median) evaluated together, as well as ctDNA status with tumor CD8 or cell programmed death ligand 1 expression, were more predictive of survival than ctDNA alone. Tumor bulk RNA-seq expression patterns identified gene expression at baseline associated with recurrence.ConclusionsThis study represents the largest assessment of ctDNA and other baseline tumor and peripheral biomarkers for predicting recurrence-free survival in patients with resected melanoma receiving adjuvant immunotherapy. ctDNA alone and in combination with more established biomarkers predicted recurrence-free and distant metastasis-free survival and has potential utility for assessing and monitoring the risk of recurrence in patients with resected melanoma treated with immunotherapy in the adjuvant setting.Trial registration numberNCT03068455.

The tumor immune composition influences prognosis and treatment sensitivity in lung cancer. The presence of effective adaptive immune responses is associated with increased clinical benefit after immune checkpoint blockers. Conversely, immunotherapy resistance can occur as a consequence of local T-cell exhaustion/dysfunction and upregulation of immunosuppressive signals and regulatory cells. Consequently, merely measuring the amount of tumor-infiltrating lymphocytes (TILs) may not accurately reflect the complexity of tumor-immune interactions and T-cell functional states and may not be valuable as a treatment-specific biomarker. In this work, we investigate an immune-related biomarker (PhenoTIL) and its value in associating with treatment-specific outcomes in non-small cell lung cancer (NSCLC). PhenoTIL is a novel computational pathology approach that uses machine learning to capture spatial interplay and infer functional features of immune cell niches associated with tumor rejection and patient outcomes. PhenoTIL’s advantage is the computational characterization of the tumor immune microenvironment extracted from H&E-stained preparations. Association with clinical outcome and major non-small cell lung cancer (NSCLC) histology variants was studied in baseline tumor specimens from 1,774 lung cancer patients treated with immunotherapy and/or chemotherapy, including the clinical trial Checkmate 057 (NCT01673867).

BackgroundMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that suppress T-cell effector function and proliferation. Elevated blood MDSCs are associated with poor outcomes across multiple tumor types in clinical studies and are suggested to be an immunotherapy resistance mechanism. Several chemotherapeutic agents used in conventional cancer chemotherapy regimens reduce MDSC numbers in preclinical models, however, their impact on human MDSC phenotype and function is less. In this study, we show that Cisplatin modulates the expression of specific markers of human MDSCs while Carboplatin and Cisplatin revert their suppressive activity on CD8+ T cells.MethodsHuman CD14+ monocytes were isolated from frozen PBMCs of healthy donors using positive selection. Autologous CD8+T cells were purified via negative selection. To generate MDSCs, CD14+ monocytes were cultured in RPMI medium supplemented with 10% FBS, with cytokine mixtures, which consist of GM-CSF, IL-6 and TGF-β, for 7 days. At day 4, chemotherapeutic agents were added to the culture. At day 7, the cells were harvested and co-cultured with activated and dye-labelled (anti-CD3/CFSE) CD8+ T cells for 72h. Cells were analyzed by flow cytometry to assess proliferation and supernatants were collected for cytokine expression analyses.ResultsIn vitro generated MDSCs show increased expression of CD33, CD11b and PD-L1 and reduced expression of HLA-DR and CD68 on the surface relative to control CD14+ cells. Cisplatin treatment inhibits the cell growth of these MDSCs and induces apoptosis during the differentiation stage in a dose dependent manner. Cisplatin-treated MDSCs also display a modulation of their phenotype (increased expression of HLA-DR and downregulation of PD-L1). Additionally, Cisplatin and Carboplatin abrogate the MDSC suppressive activity as shown by increased CD8+ T cell proliferation and IFN-g secretion in co-culture assays. Cisplatin also increased the secretion of other T cell related cytokines while reducing the secretion of myeloid-related cytokines. Other commonly used chemotherapeutic agents tested in this study, such as Paclitaxel and Pemetrexed did not show any effects on reversing either MDSC phenotype or suppressive activity.ConclusionsOur data suggest that Cisplatin may reduce MDSC levels in cancer patients through depletion as well as reversing their phenotype and suppressive function. Carboplatin did not affect the MDSC phenotype but had a significant impact in reducing their suppressive capacity. Taken together, our observations suggest that platinum-based chemotherapy have a modulatory effect on MDSCs which may improve immunotherapy efficacy in patients with high levels of these cells through depletion and reversion of their inhibitory activity.

BackgroundPathologic response assessment after neoadjuvant treatment is the potential analog to radiographic response for advanced disease, with regard to study design, clinical care, and accelerated regulatory approvals. A standardized system for assessing degree of pathologic response in the primary tumor (PT) and lymph nodes (LNs) as a survival surrogate is an unmet need. It is also a prerequisite for determining whether patients with versus without LN involvement benefit from neoadjuvant therapy. Here, in a pre-specified exploratory analysis from CheckMate 816, we report the first in-depth assessment of the full spectrum of percent residual viable tumor (RVT; beyond pathologic complete response) in both the PT and LNs and its association with event-free survival (EFS). This study represents the first prospective use of such a pan-tumor scoring system in a phase 3 registrational trial.MethodsPathologic response was prospectively assessed in the randomized phase 3 study of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in patients with resectable non-small cell lung carcinoma. Percentages of RVT, regression, and necrosis were quantified (0%-100%) in the PT and LNs using pan-tumor immune-related pathologic response criteria (irPRC). Pathologic features scored using this system were tested for association with EFS. An exploratory comparison between pathologic response, radiographic response, and circulating tumor DNA (ctDNA) clearance was performed.ResultsIn both treatment arms and regardless of pathologic evidence of LN involvement, EFS was improved in patients with 0% versus >0% RVT-PT (HR=0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (AUC=0.74); 2-year EFS rates were 90%, 60%, 57%, and 39% for patients with 0%-5%, >5%-30%, >30%-80%, and >80% RVT, respectively. Each 1% increase in RVT associated with a 0.017 increase in HR for EFS. Combining pathologic response from PT+LNs helped differentiate outcomes. An increase in%necrosis was not observed in paired pre- and on-treatment specimens in either treatment arm. Further, necrosis within the on-treatment specimens was associated with lower EFS rates, arguing against necrosis as a histologic feature of treatment effect. When pathologic response was compared to radiographic response and ctDNA clearance, pathologic response best approximated EFS.ConclusionsPercent RVT associates with improved EFS, supporting pathologic response as an emerging survival surrogate. Given the prognostic value of%RVT, its assessment using routine surgical pathology workflows, and a scoring system generalizable to any solid tumor type, it is also anticipated to become a biomarker for guiding subsequent adjuvant therapy. Further assessment of clinically-relevant%RVT cutoffs in PT+LN is warranted.AcknowledgementsFunding for this study was provided by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.Trial RegistrationNCT02998528Ethics ApprovalThis study was approved by the Johns Hopkins University Institutional Review Board.