scholarly journals 926 Immune profiling of KEAP1-deficient NSCLC: development of therapeutic strategies to overcome resistance to immunotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A971-A971
Author(s):  
Ana Galan-Cobo ◽  
Yu Qian ◽  
Fuduan Peng ◽  
Daniel McGrail ◽  
Fahao Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Early Stage ◽  
Therapy Response ◽  
Immune Checkpoint Blockade ◽  
Loss Of Function ◽  
Kras Mutations ◽  
Early Stage Lung Cancer ◽  
Nk T Cells ◽  
Md Anderson

BackgroundIn LUAD, KEAP1 is the third most common tumor suppressor and loss-of-function mutations in KEAP1 commonly co-occur with STK11/LKB1 and KRAS mutations. KEAP1 protein that regulates the degradation of the antioxidant transcription factor NRF2. The role of STK11/LKB1 mutations in immunotherapy resistance has been characterized, however the mechanistic understanding of KEAP1 deficiency in shaping LUAD phenotype and therapy response is still very limited. Recent clinical data has been reported suggesting that mutations in STK11/LKB1 and KEAP1 are strongly associated with immune checkpoint blockade resistance in LUAD, particularly those with KRAS mutations. Nevertheless, the biology of KEAP1-deficient tumors and the immune suppression mechanisms are to be characterized.MethodsWe have first validated response to anti-PD1 treatment in vivo using subcutaneous murine models, and performed a deep profiling and characterization of tumor microenvironment (TME) heterogeneity of KRAS-mutant (K) and LKB1 (KL), and/or KEAP1 deficient (KK and KLK) tumors using single-cell RNA sequencing (scRNA-seq) and multiplex staining. Data from pre-clinical models has been used to survey the immune genomic data available from the MD Anderson ICON study (a cohort of early stage lung cancer untreated 148 resected tumors) and TCGA lung cohorts to further validate our findings.ResultsWhile K tumors showed significant response to anti-PD1 treatment, KEAP1 loss completely impaired therapeutic response to this immunotherapy. KEAP1-deficient tumors were characterized by low immune infiltration while displayed an enrichment of cancer associated fibroblasts (CAFs) and endothelial cells. scRNA-seq data indicated a significant reduction of T cell infiltration, in particularly, CD8 and NK T cells, pronounced decreased of B cell population and a marked M2 macrophages polarization. Likewise, IHC and multiplex analysis of CD3 and F4/80 markers confirmed these previous findings. In TCGA lung cancer cohort, CD8B expression was dramatically decreased while MIF (macrophage migration inhibitory factor) was upregulated in KK compared to K LUADs tumors, and expression of KEAP1 inversely correlated with CD163, ARG2 and IL10, which are mainly secreted by macrophages. Concordantly, KEAP1-deficient pre-clinical tumors showed a significant upregulation of MIF expression and secretion, and CRISPR-Cas9 deletion of MIF dramatically impaired in vivo tumor growth in KK and KLK but not in K or KL models.ConclusionsThese findings indicate that loss of KEAP1, alone or in combination with STK11/LKB1 alterations, unfavorably reprograms TME. These changes appear to be mediated at least in part through MIF upregulation, providing a potential therapeutic strategy for overcoming KEAP1-dependent resistance to immunotherapy.

PD-1 Blockade in Early-Stage Lung Cancer

2019 ◽  
Vol 70 (1) ◽  
pp. 425-435 ◽  
Author(s):  
Samuel Rosner ◽  
Joshua E. Reuss ◽  
Patrick M. Forde
Keyword(s):  
Lung Cancer ◽  
Early Stage ◽  
Immune Checkpoint Blockade ◽  
Advanced Lung Cancer ◽  
Early Stage Lung Cancer ◽  
Early Results ◽  
Stage Disease ◽  
Relapse Rates ◽  
Stage Lung Cancer

Early-stage non–small cell lung cancer is a potentially curable disease, but with relapse rates exceeding 50% with standard treatments, this is a patient population in critical need of therapy innovation. Immunotherapy with immune checkpoint blockade has revolutionized the treatment strategy for advanced lung cancer. However, the role of this therapy in earlier-stage disease is largely unknown. The study of immunotherapy in earlier-stage disease has many advantages, including assessment of pathologic response and incorporation of translational scientific analyses to evaluate antitumor immune responses. Multiple clinical trials are currently under way, with promising early results.

scholarly journals FlowCell-enriched circulating tumor cells as a predictor of lung cancer metastasis

Human Cell ◽  
2021 ◽  
Author(s):  
Yan Lu ◽  
Yushuang Zheng ◽  
Yuhong Wang ◽  
Dongmei Gu ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Metastasis ◽  
Lung Tumor ◽  
Early Stage ◽  
High Rate ◽  
Early Stage Lung Cancer ◽  
Lung Cancer Metastasis ◽  
Number Of Patients

AbstractLung cancer is the most fetal malignancy due to the high rate of metastasis and recurrence after treatment. A considerable number of patients with early-stage lung cancer relapse due to overlooked distant metastasis. Circulating tumor cells (CTCs) are tumor cells in blood circulation that originated from primary or metastatic sites, and it has been shown that CTCs are critical for metastasis and prognosis in various type of cancers. Here, we employed novel method to capture, isolate and classify CTC with FlowCell system and analyzed the CTCs from a cohort of 302 individuals. Our results illustrated that FlowCell-enriched CTCs effectively differentiated benign and malignant lung tumor and the total CTC counts increased as the tumor developed. More importantly, we showed that CTCs displayed superior sensitivity and specificity to predict lung cancer metastasis in comparison to conventional circulating biomarkers. Taken together, our data suggested CTCs can be used to assist the diagnosis of lung cancer as well as predict lung cancer metastasis. These findings provide an alternative means to screen early-stage metastasis.

scholarly journals P04.10 Relapsed or Metastatic Organotropism in Early Stage Lung Cancer after Radical Surgery

2021 ◽  
Vol 16 (3) ◽  
pp. S264-S265
Author(s):  
F. Xu ◽  
L. Yang ◽  
C. Liu ◽  
J. Ying ◽  
Y. Wang
Keyword(s):  
Lung Cancer ◽  
Radical Surgery ◽  
Early Stage ◽  
Early Stage Lung Cancer ◽  
Stage Lung Cancer

scholarly journals Structural and functional radiomics for lung cancer

2021 ◽  
Author(s):  
Guangyao Wu ◽  
Arthur Jochems ◽  
Turkey Refaee ◽  
Abdalla Ibrahim ◽  
Chenggong Yan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Strategy ◽  
Early Stage ◽  
Quality Data ◽  
Clinical Implementation ◽  
Early Stage Lung Cancer ◽  
Treatment Response Evaluation ◽  
Advanced Stage Lung Cancer ◽  
Stage Lung Cancer

Abstract Introduction Lung cancer ranks second in new cancer cases and first in cancer-related deaths worldwide. Precision medicine is working on altering treatment approaches and improving outcomes in this patient population. Radiological images are a powerful non-invasive tool in the screening and diagnosis of early-stage lung cancer, treatment strategy support, prognosis assessment, and follow-up for advanced-stage lung cancer. Recently, radiological features have evolved from solely semantic to include (handcrafted and deep) radiomic features. Radiomics entails the extraction and analysis of quantitative features from medical images using mathematical and machine learning methods to explore possible ties with biology and clinical outcomes. Methods Here, we outline the latest applications of both structural and functional radiomics in detection, diagnosis, and prediction of pathology, gene mutation, treatment strategy, follow-up, treatment response evaluation, and prognosis in the field of lung cancer. Conclusion The major drawbacks of radiomics are the lack of large datasets with high-quality data, standardization of methodology, the black-box nature of deep learning, and reproducibility. The prerequisite for the clinical implementation of radiomics is that these limitations are addressed. Future directions include a safer and more efficient model-training mode, merge multi-modality images, and combined multi-discipline or multi-omics to form “Medomics.”

scholarly journals Anatomical variants of pulmonary segments and uni-portal thoracoscopic segmentectomy for lung cancer in a patient with Kartagener syndrome: a case report

2021 ◽  
Author(s):  
Di Zhou ◽  
Ye Tian ◽  
Yao Lu ◽  
Xueying Yang
Keyword(s):  
Lung Cancer ◽  
Rare Variants ◽  
Sagittal Plane ◽  
Early Stage ◽  
Situs Inversus Totalis ◽  
Middle Lobe ◽  
The Body ◽  
Kartagener Syndrome ◽  
Early Stage Lung Cancer ◽  
Cancer Lesion

AbstractSitus inversus totalis (SIT) is an extremely uncommon congenital disease where the major organs of the body are transposed through the sagittal plane. Kartagener syndrome is a complication of SIT with immotility of bronchial cilia, bronchiectasis, and chronic sinusitis. There is no report describing patients with Kartagener syndrome who accept uni-portal segmentectomies for lung cancer in past studies. Here we report a 74-year-old female patient with both Kartagener syndrome and a small early-stage lung cancer lesion located in the apical segment of the left upper lobe (LS1). The pulmonary segment anatomy of the left upper lobe in this case, which had very rare variants, was presented and interpreted in detail. This patient underwent an anatomic segmentectomy to the LS1 and a partial excision to the left middle lobe with bronchiectasis through a single 3 cm length incision. We believe that the case can give surgeons some experience and inspiration.

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