scholarly journals Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer

2019 ◽  
Vol 216 (4) ◽  
pp. 982-1000 ◽  
Author(s):  
Bo Gong ◽  
Kazuma Kiyotani ◽  
Seiji Sakata ◽  
Seiji Nagano ◽  
Shun Kumehara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transmembrane Domain ◽  
Xenograft Model ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Small Cell Lung ◽  
Antibody Treatment ◽  
Nsclc Patients

Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non–small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti–PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1–resistant NSCLC patients. These secreted PD-L1 variants worked as “decoys” of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti–PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.

scholarly journals 710 Differences in the susceptibility of human small cell lung cancer variants to NK cell-mediated lysis can be overcome with the addition of N803 (IL-15 superagonist)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A739-A739
Author(s):  
Kristen Fousek ◽  
Lucas Horn ◽  
Haiyan Qin ◽  
Bobby Reddy ◽  
Lennie Sender ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Nk Cells ◽  
Cell Lung Cancer ◽  
Nk Cell ◽  
Xenograft Model ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Cell Phenotype ◽  
Small Cell Lung

BackgroundSmall cell lung cancer (SCLC) is a highly aggressive tumor with a 5-year survival rate of less than 5%. Traditionally characterized as a neuroendocrine (NE) cancer, several subtypes have now been identified which vary in their phenotypic and transcriptional profiles. Classical NE tumors are molecularly defined as ASCL1+ or NEUROD1+ and exhibit an epithelial phenotype, expressing cytokeratin and E-cadherin (E-Cad). In contrast, non-classical variants express POU2F3 or YAP1 and are enriched in mesenchymal features, such as high levels of vimentin (Vim). Prior studies describe that non-NE variants of SCLC are less susceptible to chemotherapy and may arise via therapeutic selection. With the addition of immune checkpoint blockade to first-line chemotherapy for the treatment of advanced SCLC, understanding whether SCLC variants respond differently to immunotherapy is crucial.MethodsWe utilized a range of pre-clinical models to investigate whether molecular and phenotypic variants of SCLC differ in their susceptibility to immune-mediated lysis. Following extensive characterization at the RNA and protein levels for expression of ASCL1, NEUROD1, POU2F3, YAP1, epithelial E-Cad, mesenchymal Vim, and other markers of cell phenotype, a panel of cells including each variant subtype were selected for further study.ResultsUpon exposure to healthy donor effector NK cells, the more epithelial cells were highly susceptible to NK-mediated cytotoxicity while all mesenchymal SCLC cells remained highly refractory to NK-mediated lysis. This prompted us to investigate immunotherapy approaches such as the addition of N803, a mutant IL-15 superagonist, to improve the activation and proliferation of NK cells. In a xenograft model utilizing the mesenchymal YAP1+ H841 cell line subcutaneously implanted into nude mice devoid of all immune cells except for NK cells, we observed that the weekly administration of N803 resulted in a significant increase in the number of activated NK cells within the spleens of treated mice. Additionally, NK cells from treated mice produced significantly higher levels of IFN-gamma and granzyme B, resulting in a significant decrease in overall tumor burden.ConclusionsOur data indicates that N803-activated NK cells effectively mediate lysis of SCLC across all variant types, including those previously completely refractory to traditional NK cell lysis. These results highlight the potential of N803 as a novel immune-based intervention for the treatment of all variants of SCLC.Ethics ApprovalPBMCs were obtained from healthy donors at the NIH Clinical Center Blood Bank (NCT00001846). All animal studies were approved and conducted in accordance with an IACUC-approved animal protocol (LTIB-57) with the approval the NIH/NCI Institutional Animal Care and Use Committee.

scholarly journals Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer

2021 ◽  
Vol 9 (8) ◽  
pp. e002891
Author(s):  
Marcelo V Negrao ◽  
Ferdinandos Skoulidis ◽  
Meagan Montesion ◽  
Katja Schulze ◽  
Ilze Bara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.ConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

scholarly journals Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1794
Author(s):  
Alice Indini ◽  
Erika Rijavec ◽  
Francesco Grossi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Circulating Biomarkers ◽  
Small Cell Lung ◽  
Nsclc Patients

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (PD)-1 protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, have revolutionized the management of patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only a small portion of NSCLC patients respond to these agents. Furthermore, although immunotherapy is usually well tolerated, some patients experience severe immune-related adverse events (irAEs). Liquid biopsy is a non-invasive diagnostic procedure involving the isolation of circulating biomarkers, such as circulating tumor cells (CTC), cell-free DNA (cfDNA), and microRNAs (miRNAs). Thanks to recent advances in technologies, such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR), liquid biopsy has become a useful tool to provide baseline information on the tumor, and to monitor response to treatments. This review highlights the potential role of liquid biomarkers in the selection of NSCLC patients who could respond to immunotherapy, and in the identification of patients who are most likely to experience irAEs, in order to guide improvements in care.

scholarly journals 1318P Association between soluble PD-L1 and prognosis of non-small cell lung cancer (NSCLC) patients treated with immunotherapy

2020 ◽  
Vol 31 ◽  
pp. S851
Author(s):  
C. Dellepiane ◽  
S. Coco ◽  
M.G. Dal Bello ◽  
G. Rossi ◽  
E. Rijavec ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients
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