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Background: Despite its early success, immunotherapy focused on removing T-cell inhibition does not achieve the desired effect in most patients. New strategies that target antigen-driven T-cell activation are needed to improve immunotherapy outcomes. However, a comprehensive analysis of synthetic drivers of T-cells is greatly lacking in lung adenocarcinoma (LUAD) and other types of tumors., Methods: We comprehensively evaluated the patterns of LUAD patients based on T -cell synthetic drivers by unsupervised clustering analysis. A risk model was constructed using Lasso Cox regression analysis. The predicted survival and immunotherapy efficacy of the model was validated by independent cohorts. Finally, single-cell sequencing analysis, and a series of in vitro experiments were conducted to explore the role of lactate dehydrogenase A (LDHA) in the malignant progression of LUAD., Results: Patients in the high-risk group were characterized by survival disadvantage, a "cold" immune phenotype, and by not having benefitted from immunotherapy. LDHA was shown to promote LUAD cell proliferation, cell cycle, invasion, and migration. Secondly, we found that LDHA induced NF-κB pathway activation, tyrosine kinase inhibitor resistance and immunosuppressant microenvironment. Finally, LDHA was found to be highly expressed in fibroblasts, which may be involved in promoting TKI resistance and mediating the immune escape., Conclusion: This study revealed that the T-cell synthetic driver-associated prognostic model developed herein significantly predicted prognosis and immunotherapy efficacy in LUAD. We further investigated the role of LDHA in the malignant phenotype of tumor cells and tumor microenvironment remodeling, providing a promising and novel therapeutic strategy for LUAD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype., Experimental Design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and the combined efficacy of IL6 inhibition and anti-PD-1 therapy. Corresponding in vitro studies used EGFR-mutant human cell lines and clinical specimens., Results: We identified that EGFR-mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL6 secretion. In EGFR-mutant GEMMs, IL6 depletion enhanced activation of infiltrating natural killer (NK)- and T-cell subpopulations and decreased immunosuppressive regulatory T and Th17 cell populations. Inhibition of IL6 increased NK- and T cell-mediated killing of human osimertinib-resistant EGFR-mutant NSCLC tumor cells in cell culture. IL6 blockade sensitized EGFR-mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells., Conclusions: These data indicate that IL6 is upregulated in EGFR-mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T- and NK-cell function. IL6 blockade enhanced antitumor immunity and efficacy of anti-PD-1 therapy warranting future clinical combinatorial investigations., (©2023 American Association for Cancer Research.)

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation., Competing Interests: Declaration of interests J.V.H. serves on advisory committees for DAVA Oncology, Regeneron, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, and Chugai Pharmaceuticals; receives research support from Takeda, AstraZeneca, Boehringer-Ingelheim, and Spectrum; and receives royalties and licensing fees from Spectrum Pharmaceuticals. D.L.G. serves as an advisor/consultant for Sanofi, GlaxoSmithKline, Janssen Research & Development, Ribon Therapeutics, Mitobridge, Eli Lilly, Menarini, and Napa Therapeutics and receives research funding from Janssen Research & Development, Takeda, AstraZeneca, Mitobridge, Ribon Therapeutics, NGM Biopharmaceuticals, Boehringer Ingelheim, and Mirati Therapeutics. S.S.K. reports research support from Boehringer Ingelheim, Janssen, MiNA Therapeutics, MiRXES, and Taiho Therapeutics and honoraria from Boehringer Ingelheim, Bristol Meyers Squibb, AstraZeneca, Chugai Pharmaceutical, and Takeda Pharmaceuticals, all outside of the submitted work. X.L. receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen, Blueprint Medicines, Sensei Biotherapeutics, and AbbVie and received research funding from Eli Lilly, EMD Serono, Regeneron, and Boehringer Ingelheim. M.B.N. and J.P.R. receive royalties and licensing fees from Spectrum Pharmaceuticals. M.B.N. and J.V.H. have filed a patent for CD70 targeting in EGFR TKI-resistant NSCLC (17/611,019). J.P.R. is currently a full-time employee and shareholder of AstraZeneca. Y.Y.E. discloses research support from AstraZeneca, Takeda, Eli Lilly, Xcovery, Tuning Point Therapeutics, BluPrint, and Elevation Oncology; an advisory role for AstraZeneca, Eli Lilly, Takeda, Spectrum, Bristol Myers Squibb, and Turning Point; and accommodation expenses from Eli Lilly. H.U. receives research support from Takeda Pharmaceuticals and Boehringer Ingelheim. S.H. receives consulting fees from AstraZeneca and Boehringer Ingelheim and speaker fees from Qiagen., (Copyright © 2023. Published by Elsevier Inc.)

Background: Despite the robotic surgery is widely applied, sleeve lobectomy for lung cancer using the Da Vinci surgical system is still less performed. We described a sleeve lobectomy for adenocarcinoma located at the left lower lobe using the Da Vinci surgical system., Case Presentation: A case of 57-year old female referred to our hospital. Computed tomography scan showed an occupation located at the left lower lobe and adenocarcinoma project from the lobe bronchus was diagnosed by bronchoscope examination. A sleeve lobectomy was performed using the Da Vinci surgical system and the postoperative recovery was uneventful., Conclusions: Robotic thoracic surgery is feasible to perform sleeve lobectomy inspite of inadequate experience.

Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of KRAS occur frequently in, and are thought to be a primary driver of the development of, non-small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant KRAS cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and KRAS. Mutational activation of KRAS modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic KRAS repressed cellular FADD-like interleukin 1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame KRAS-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant KRAS cells without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC.