tbuckley/cabot-search huggingface dataset:
Conserved helical motifs in the IKZF1 disordered region mediate NuRD interaction and transcriptional repression
Authors: Tianyi Zhang, Yi-Fang Wang, Alex Montoya, Ilinca Patrascan, Nehir Nebioglu, Husayn A Pallikonda, Radina Georgieva, James WD King, Holger B Kramer, Pavel V Shliaha, David S. Rueda, Matthias Merkenschlager
Journal: Blood (2024)

The transcription factor IKZF1 is essential for B cell development, and recurrently mutated in human B-ALL. IKZF1 has been ascribed both activating and repressive functions via interactions with coactivator and corepressor complexes, but the relative abundance of IKZF1-associated coregulators and their contribution to IKZF1-mediated gene regulation are not well understood. To address this, we performed an unbiased identification of IKZF1-interacting proteins in pre-B cells and found that IKZF1 interacts overwhelmingly with corepressors and heterochromatin-associated proteins. Time-resolved analysis of transcription and chromatin state identified transcriptional repression as the immediate response to IKZF1 induction. Transcriptional repression preceded transcriptional activation by several hours, manifesting as a decrease in the fraction of transcriptional bursts at the single molecule level. Repression was accompanied by a rapid loss of chromatin accessibility and reduced levels of H3K27ac particularly at enhancers. We identified highly conserved helical motifs within the intrinsically disordered region in IKZF1 that mediate its association with the NuRD corepressor complex through critical "KRK" residues that bind the NuRD subunit RBBP4, a mechanism shared with the TFs FOG1, BCL11A, and SALL4. Functional characterization reveals this region is necessary for to the efficient silencing of target genes and antiproliferative functions of IKZF1 in B-ALL.
The hepcidin-ferroportin axis modulates liver endothelial cell BMP expression to influence iron homeostasis in mice
Authors: Allison L Fisher, Sydney Phillips, Chia-Yu Wang, Joao A Paulo, Xia Xiao, Yang Xu, Gillian A Moschetta, Yongqiang Xue, Joseph D. Mancias, Jodie L. Babitt
Journal: Blood (2024)
Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation
Authors: Anita Kumar, Jacob D. Soumerai, Jeremy S Abramson, Jeffrey A. Barnes, Philip C Caron, Shalini Chhabra, Maria Chabowska, Ahmet Dogan, Lorenzo Falchi, Clare Grieve, J. Erika Haydu, Patrick Connor Johnson, Ashlee Joseph, Hailey Kelly, Alyssa Labarre, Jennifer K Lue, Rosalba Martignetti, Joanna Mi, Alison J Moskowitz, Colette N Owens, Sean Plummer, Madeline Puccio, Gilles A. Salles, Venkatraman E Seshan, Elizabeth Simkins, Natalie Slupe, Honglei Zhang, Andrew D. Zelenetz
Journal: Blood (2024)

Background: TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ³11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483
Saliva from persons with hemophilia A triggers coagulation via extrinsic tenase complexes
Authors: Johannes Thaler, Carla Tripisciano, Daniel Kraemmer, Chi Hau, Nazanin Samadi, Wolfram Ruf, Ingrid Pabinger, Paul Knöbl, Rienk Nieuwland, Cihan Ay
Journal: Blood (2024)
IGF1R signaling in perinatal mesenchymal stem cells determines definitive hematopoiesis in bone marrow
Authors: Qi Lou, Kaizheng Jiang, Xiaoqi Wang, Yuan Pan, Guo Qiu, Binghuo Wu, Lisha Yuan, Siyu Xie, Jian Chen, Quanhui Xu, Meng Zhao, Linjia Jiang
Journal: Blood (2024)
Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors
Authors: Stefano Comazzetto, Daniel Cassidy, Andrew W DeVilbiss, Elise Jeffery, Bethany Ottesen, Amanda Reyes, Animesh Paul, Suraj Bansal, Stephanie Z Xie, Sarah Muh, Thomas Mathews, Brandon Chen, Zhiyu Zhao, Sean J. Morrison
Journal: Blood (2024)

Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development, partly by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter from hematopoietic cells depleted ascorbate to undetectable levels in HSCs and MPPs without altering plasma ascorbate levels. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potentials of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate deficiency confers MPPs with long-term self-renewal potential.
MSI2 mediates WNT/β-Catenin pathway function in hematopoietic stem cells
Authors: Huifang Zhang, Ruixue Guo, Zhenfen Li, Rui Ma, Shina Xu, Le Yin, Hongkai Zhu, Zineng Huang, Cheng Xing, Yunlong Yang, Yulin Pu, Zhao Cheng, Jing Liu, Hongling Peng, Yue Sheng
Journal: Leukemia (2024)
Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia
Authors: Ziwei Luo, Chencen Lin, Chuwei Yu, Changxian Yuan, Wenyong Wu, Xiaowei Xu, Renhong Sun, Yan Jia, yafang wang, Jie Shen, Dingyan Wang, Sinan Wang, Hualiang Jiang, Biao Jiang, Xiaobao Yang, Chengying Xie
Journal: Cancer Research (2024)

Abstract SOS1 is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR-ABL in leukemogenesis. Despite this, small molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 PROTAC SIAIS562055, which was designed by connecting a CRBN ligand to an analogue of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior anti-proliferative activity compared to small molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR-ABL+ CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR-ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary CML patient samples. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an eﬀective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia.
SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Brianna R. Daley, Nancy E. Sealover, Bridget A. Finniff, Jacob M. Hughes, Erin Sheffels, Daniel Gerlach, Marco H. Hofmann, Kaja Kostyrko, Joseph P. LaMorte, Amanda Linke, Zaria Beckley, Andrew M. Frank, Robert E. Lewis, Matthew D. Wilkerson, Clifton Dalgard, Robert L. Kortum
Journal: Cancer Research (2024)

Abstract The clinical effectiveness of KRASG12C inhibitors (G12Ci) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. Here, we identified targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. G12Ci drug tolerant persister (DTP) cells showed up to a 3-fold enrichment of tumor initiating cells (TIC), suggestive of a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limited the clinical effectiveness of G12Ci, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci, consistent with clinical G12Ci resistance seen with these co-mutations. Treatment with SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. Together, these data suggest that targeting SOS1 could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.
Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes
Authors: Laura Kuett, Alina Bollhagen, Sandra Tietscher, Bettina Sobottka, Nils Eling, Zsuzsanna Varga, Holger Moch, Natalie de Souza, Bernd Bodenmiller
Journal: Cancer Research (2024)

Abstract Breast cancer is the most commonly diagnosed cancer in women, with distant metastasis being the main cause of breast cancer-related deaths. Elucidating the changes in the tumor and immune ecosystems that are associated with metastatic disease is essential to improve understanding and ultimately treatment of metastasis. Here, we developed an in-depth, spatially resolved single-cell atlas of the phenotypic diversity of tumor and immune cells in primary human breast tumors and matched distant metastases, using imaging mass cytometry to analyze a total of 75 unique antibody targets. While the same tumor cell phenotypes were typically present in primary tumors and metastatic sites, suggesting a strong founder effect of the primary tumor, their proportions varied between matched samples. Notably, the metastatic site did not influence tumor phenotype composition, except for the brain. Metastatic sites exhibited a lower number of immune cells overall, but had a higher proportion of myeloid cells as well as exhausted and cytotoxic T cells. Myeloid cells showed distinct tissue-specific compositional signatures and increased presence of potentially matrix remodeling phenotypes in metastatic sites. This analysis of tumor and immune cell phenotypic composition of metastatic breast cancer highlights the heterogeneity of the disease within patients and across distant metastatic sites, indicating myeloid cells as the predominant immune modulators that could potentially be targeted at these sites.
AKT and the Hallmarks of Cancer
Authors: Eleonora Sementino, Dalal Hassan, Alfonso Bellacosa, Joseph R. Testa
Journal: Cancer Research (2024)

Abstract Nearly a quarter century ago, Hanahan and Weinberg conceived six unifying principles explaining how normal cells transform into malignant tumors. Their provisional set of biological capabilities acquired during tumor development  cancer hallmarks  would evolve to fourteen tenets as knowledge of cancer genomes, molecular mechanisms, and the tumor microenvironment expanded, most recently adding four emerging enabling characteristics: phenotypic plasticity, epigenetic reprogramming, polymorphic microbiomes, and senescent cells. AKT kinases are critical signaling molecules that regulate cellular physiology upon receptor tyrosine kinases and phosphatidylinositol 3-kinase activation. The complex branching of the AKT signaling network involves several critical downstream nodes that significantly magnify its functional impact, such that nearly every organ system and cell in the body may be affected by AKT activity. Conversely, tumor intrinsic dysregulation of AKT can have numerous adverse cellular and pathological ramifications, particularly in oncogenesis, as multiple tumor suppressors and oncogenic proteins regulate AKT signaling. Herein, we review the mounting evidence implicating the AKT pathway in the aggregate of currently recognized hallmarks of cancer underlying the complexities of human malignant diseases. The challenges, recent successes, and likely areas for exciting future advances in targeting this complex pathway are also discussed.
Outcomes of the American Board of Dermatology focused Practice Improvement program 2016-2023
Authors: Erik Stratman, Stanley Miller, Murad Alam, Sacharitha Bowers, Erin F Mathes, Kiran Motaparthi, Andrea Murina, Rachelle Naridze, Gideon P Smith, Deirdre A Stolmeier, Adam Sutton, Melissa Williams, Randy Roenigk
Journal: Journal of the American Academy of Dermatology (2024)
Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial
Authors: Sunjae Lee, Bethlehem Arefaine, Neelu Begum, Marilena Stamouli, Elizabeth Witherden, Merianne Mohamad, Azadeh Harzandi, Ane Zamalloa, Haizhuang Cai, Roger Williams, Mike Curtis, Lindsey A Edwards, Shilpa Chokshi, Adil Mardinoglu, Gordon Proctor, David Moyes, Mark J McPhail, Debbie L Shawcross, Mathias Uhlen, Saeed Shoaie, Vishal C Patel
Journal: Journal of Hepatology (2024)
Association of Intellectual and Developmental Disabilities With Worse Outcomes After Surgical Treatment of Cancer
Authors: Vivian Resende, Selamawit Woldesenbet, Erryk Katayama, Muhammad Musaab Munir, Henrique Araújo Lima, Mujtaba Khalil, Karol Rawicz-Pruszyński, Muhammad Muntazir Mehdi Khan, Usama Waqar, Parit Mavani, Yutaka Endo, Timothy M. Pawlik
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Patients with intellectual and developmental disabilities (IDD) face unique challenges resulting in disparities in their health care. We sought to define the effect that IDD had on achievement of a “textbook outcome” (TO) following a cancer operation among a nationally representative cohort of patients. Methods: Data on patients who underwent surgery for a malignant indication, including lung, breast, liver, biliary tract, pancreas, and colorectal, between 2014 and 2020 were extracted from the 100% Medicare Standard Analytical Files database. The association of IDD with TO (defined as the absence of postoperative complications, extended length of stay, 90-day readmission, and 90-day mortality), expenditures, and discharge status was assessed using multivariable logistic regression. Results: Among 500,472 Medicare beneficiaries, 4,326 (0.9%) with IDD had a cancer diagnosis (breast, n=481; lung, n=419; hepatobiliary, n=194; pancreas, n=145; colorectal, n=3,087). Although overall incidence of TO was 50.5%, patients with IDD were less likely to achieve a TO than those without (37.1% vs 50.6%, respectively; odds ratio [OR], 0.50; 95% CI, 0.46–0.53; P &lt;.001). On multivariable regression, patients with IDD had higher odds of a postoperative complication (OR, 1.53; 95% CI, 1.43–1.64), extended length of stay (OR, 2.06; 95% CI, 1.93–2.21), 90-day readmission (OR, 1.15; 95% CI, 1.07–1.24), 90-day mortality (OR, 1.90; 95% CI, 1.70–2.13), and discharge to a skilled nursing facility (OR, 4.28; 95% CI, 3.97–4.62) (all P &lt;.001). Conclusions: Patients with IDD had a much lower chance of a postoperative TO, as well as discharge to a nonhome setting. The data highlight the need to improve the care of patients with IDD to assure equitable oncologic surgical care.
First-in-human dose escalation study of the first-in-class PDE3A-SLFN12 complex inducer BAY 2666605 in patients with advanced solid tumors co-expressing SLFN12 and PDE3A.
Authors: Kyriakos P. Papadopoulos, Meredith McKean, Silvia Goldoni, Isabelle Genvresse, Marine F. Garrido, Rui Li, Gary Wilkinson, Christoph Kneip, Timothy A. Yap
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The study aims to evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12), leading to a cytotoxic response in cancer cells. Patients and Methods: This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A–SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that coexpress SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were prescreened for SLFN12 and PDE3A overexpression, and five biomarker-positive patients received ≥1 BAY 2666605 dose. Results: The most common adverse event was grade 3 to 4 thrombocytopenia in three of the five patients treated. The long half-life (&amp;gt;360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with a once-daily maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared with tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. Conclusions: Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination.
Risk of type-2-diabetes after breast cancer treatment: a population-based cohort study in Denmark
Authors: Kasper A Kjærgaard, Astrid Kousholt, Reimar W Thomsen, Kirsten M Woolpert, Henrik T Sørensen, Signe Borgquist, Deirdre Cronin-Fenton
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Purpose Data on type 2 diabetes (T2D) risk after breast cancer (BC) could guide preventive strategies. Yet, studies had limitations regarding sample size, follow-up, and contemporary treatments. We evaluated the risk of T2D after BC overall, by cancer treatment, and compared with a matched cohort of cancer-free women. Methods We assembled a population-based cohort of early-stage BC patients aged 30 years or more diagnosed during 1996-2021 in Denmark. We created a comparison cohort of 5 cancer- and T2D-free women for each BC patient, matched 6 months after BC diagnosis date on age and region. We followed both cohorts until T2D diagnosis, emigration, death, or December 31, 2022. We computed 5-year cumulative incidences and used Cox models to calculate time-varying adjusted hazard ratios (aHR) of T2D. Results Among 74 526 BC survivors and 372 630 matched cancer-free women, 5-year cumulative incidences of T2D were 3.8% (95% confidence interval [CI] = 3.7 to 3.9) and 3.3% (95% CI = 3.3 to 3.4), respectively. The aHR of T2D was elevated but attenuated over follow-up (aHR5-years = 1.20, 95% CI = 1.15 to 1.25, and aHR15-years = 1.09, 95% CI = 1.05 to 1.12). Adjuvant endocrine therapy (aHR = 1.14; 95% CI = 1.10 to 1.19), aromatase inhibitors (aHR = 1.25; 95% CI = 1.18 to 1.32), and less so tamoxifen (aHR = 1.05; 95% CI = 0.99 to 1.11), were associated with elevated risk of T2D in women with BC vs cancer-free women. Among BC patients, chemotherapy (aHR = 1.10, 95% CI = 1.03 to 1.17) and radiation therapy (right-sided aHR = 1.18, 95% CI = 1.09 to 1.27 and left-sided aHR = 1.24, 95CI = 1.15 to 1.33) were associated with increased T2D risk. Conclusion BC was associated with excess risk of T2D, although of lower magnitude than previously reported. The excess risk was temporary and related to BC treatment but could also be influenced by obesity and heightened T2D diagnostic activity.
Metabolic tumor volume assessed by 18F FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates
Authors: Filippo G. Dall'Olio, Wael Zrafi, Veronique Roelants, Valentina Ambrosini, Aloyse Fourquet, Cristina Mitea, Francesco Passiglia, Matteo Bauckneht, Gerald Bonardel, Nicole Conci, Jose Carlos Benitez, Vincenzo Arena, Céline Namour, Marie Naigeon, Isabelle Monnet, Kristi Beshiri, Delphine Hoton, Safiye Dursun, Francois Xavier. Danlos, Giulia Argalia, Mihaela Aldea, Guido Rovera, Lisa Derosa, Valerio Iebba, Hester A. Gietema, Valerie Gounant, Valérie Lacroix, Jordi Remon, Daniel Gautheret, Nathalie Chaput, Bastien Job, Patricia L. Kannouche, Monica Velasco-Nuño, Laurence Zitvogel, Eugenia Cella, José Reinaldo Chícharo de Freitas, Damien Vasseur, Mohamed Aymen Bettaieb, Marco Tagliamento, Lizza Hendriks, Antoine Italiano, David Planchard, Aurelien Marabelle, Fabrice Barlesi, Silvia Novello, Desiree De Andreis, Frank Aboubakar Nan, Andrea Ardizzoni, Gerard Zalcman, Camilo Garcia, Benjamin Besse
Journal: Clinical Cancer Research (2024)

Abstract Purpose: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). Experimental Design: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P&amp;lt;0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. Conclusion: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.