bims-meluca 2024-12-01 papers

Cancers (Basel). 2024 Nov 19. pii: 3871. [Epub ahead of print]16(22):

Prognostic Role of Inflammatory and Nutritional Biomarkers in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors Alone or in Combination with Chemotherapy as First-Line.

Antonello Veccia, Mariachiara Dipasquale, Stefania Kinspergher, Orazio Caffo.

INTRODUCTION: In recent years, several inflammation-related factors and nutritional parameters have been evaluated to develop prognostic scores as potential biomarkers in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). The aim of this study was to retrospectively investigate the prognostic role of the advanced lung cancer inflammation (ALI) index, lung immune prognostic index (LIPI), prognostic nutritional index (PNI) and systemic inflammation score (SIS) in metastatic NSCLC patients receiving ICI alone or in combination with chemotherapy.
METHODS AND PATIENTS: We retrospectively included 191 patients with advanced NSCLC who received first-line ICI with or without chemotherapy from 2017 to 2024. The association between pretreatment ALI, LIPI, PNI, and SIS and overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression models.
RESULTS: After a median follow-up of 27.7 months, significantly longer OS was associated with an ALI score > 18 vs. ≤18 (18.0 vs. 7.3 months; p = 0.00111), LIPI score 0 vs. 1 and 2 [18.9 vs. 8.2 and 4.2 months; (p = 0.001)], PNI ≥ 45 vs. <45 (22.7 vs. 9.6 months; p = 0.002), and SIS score 0 vs. 1 and 2 (27.4 vs. 7.1 and 8.6 months, respectively; p < 0.001). The OS benefit was independent of treatment (ICI vs. ICI + chemotherapy). At multivariate analysis, pretreatment albumin was positively associated with OS, while ECOG PS 1 and liver metastases were negatively associated with OS.
CONCLUSIONS: Inflammatory and nutritional biomarkers such as the ALI, LIPI, PNI, and SIS represent useful tools to prognosticate survival in metastatic lung cancer patients treated with ICI alone or in combination with chemotherapy as first-line.

Keywords: NSCLC; biomarker; chemotherapy; immune checkpoint inhibitors; inflammatory; nutritional; prognostic

DOI: https://doi.org/10.3390/cancers16223871

Cell Rep Med. 2024 Nov 19. pii: S2666-3791(24)00602-5. [Epub ahead of print] 101831

Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response.

Immune checkpoint inhibitors (ICIs) have advanced the treatment of non-small cell lung cancer (NSCLC). This study evaluates the predictive value of CD8+ T cell exhaustion in patients with lung adenocarcinoma treated with ICIs. By analyzing tumor samples from 166 patients through multiplex immunofluorescence, we quantify tumor-infiltrating lymphocytes (TILs) expressing exhaustion markers programmed cell death-1 (PD1), lymphocyte activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell immunoglobulin and mucin domain 3 (TIM3). Their co-expression is associated with ICI resistance, irrespective of programmed cell death ligand-1 (PD-L1) status. We also identify a 25-gene signature indicative of CD8+ T cell exhaustion with high predictive accuracy for ICI response. Validated using several datasets from various clinical trials, this signature accurately predicts ICI responsiveness. Our findings highlight T cell exhaustion's significance in lung adenocarcinoma responses to ICIs and suggest the 25-gene signature as a potential universal biomarker to reinforce precision medicine. This was registered under Clinical Trial registration number NCT02534649.

Keywords: LAG3; PD1; TIGIT; TIM3; biomarkers; exhaustion; immune checkpoint inhibitors; lung adenocarcinoma; tumor microenvironment

DOI: https://doi.org/10.1016/j.xcrm.2024.101831

J Exp Med. 2025 Jan 06. pii: e20231106. [Epub ahead of print]222(1):

Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.

Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D Hellmann, Étienne Caron, Susan M Kaech, Katerina Politi.

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.

DOI: https://doi.org/10.1084/jem.20231106

Curr Oncol. 2024 Oct 25. 31(11): 6673-6685

Prognostic Value of Sarcopenia in Elderly Patients with Metastatic Non-Small-Cell Lung Cancer Undergoing Radiotherapy.

Valerio Nardone, Alfonso Reginelli, Vittorio Patanè, Angelo Sangiovanni, Roberta Grassi, Anna Russo, Pierpaolo Correale, Diego Sandro Giordano, Carmine Zaccaria, Maria Paola Belfiore, Salvatore Cappabianca.

Background: Sarcopenia, a syndrome characterized by age-related loss of muscle mass and function, lacks universally accepted diagnostic criteria, particularly for its role as a prognostic factor in elderly patients with non-small-cell lung cancer (NSCLC). This study aimed to evaluate the prognostic significance of sarcopenia, assessed by psoas muscle size on baseline CT scans, in patients over 70 years of age with metastatic NSCLC. Methods: We retrospectively analyzed 85 elderly patients undergoing palliative radiation therapy between August 2022 and July 2024. Using morphometric analysis of psoas size, we investigated its correlation with overall survival (OS) and progression-free survival (PFS). Results: Our results showed that decreased psoas size was significantly associated with shorter OS and PFS, with median OS of 10 months and PFS of 4 months in sarcopenic patients compared to longer survival times in non-sarcopenic patients. Median survival of non-sarcopenic vs. sarcopenic patients was 21 ± 7 months (muscle area > median) versus 5 ± 2.3 months (muscle area < median). Multivariate analysis confirmed that psoas size, along with ECOG performance status and treatment of primary NSCLC, was a significant predictor of survival. Discussion: These findings suggest that psoas muscle size is a valuable prognostic marker for elderly NSCLC patients, potentially guiding treatment decisions and patient management. Further research is needed to validate these results and refine prognostic models for this population.

Keywords: NSCLC; elderly; morphometry; psoas muscle; sarcopenia

DOI: https://doi.org/10.3390/curroncol31110492

Biomedicines. 2024 Nov 04. pii: 2523. [Epub ahead of print]12(11):

Extracellular Vesicles from Lung Adenocarcinoma Cells Induce Activation of Different Cancer-Associated Fibroblast Subtypes.

Jessica Angelina Trejo Vazquez, Rebecca Towle, Dylan Andrew Farnsworth, Masih Sarafan, William Wallace Lockwood, Cathie Garnis.

Background: Lung cancer, including the major subtype lung adenocarcinoma (LUAD), is the leading cause of cancer deaths worldwide, largely due to metastasis. Improving survival rates requires new treatment strategies and a deeper understanding of the mechanisms that drive tumor progression within the tumor microenvironment (TME). This study investigated the impact of extracellular vesicles (EVs) derived from LUAD cells on lung fibroblasts. Methods: EVs were isolated from LUAD cell lines via ultracentrifugation and characterized using nanoparticle tracking analysis and Western blotting. Lung fibroblasts were treated with PBS, TGFβ, or EVs, and their activation was assessed through protein (Western blotting) and RNA analyses (RNA seq and RT-qPCR). Results: The results confirmed the TGFβ induced activation and showed that LUAD EVs could also activate fibroblasts, increasing cancer-associated fibroblast (CAF) markers. While EV-induced CAF activation displayed unique features, like an increase in proliferation-related genes, the EV and TGFβ treatments also shared some differentially expressed genes. The EV groups induced a higher expression of ECM remodeling and EMT-associated genes, but some of those genes were also upregulated in the TGFβ group. Mesenchymal genes POSTN and SPOCK1 were significantly upregulated in TGFβ- and EV-treated fibroblasts. Their secretion as proteins from the TGFβ- and EV-induced CAFs was not significant, confirmed through ELISA. Conclusions: These findings suggest that LUAD EVs play a role in CAF activation through both shared and distinct pathways compared to canonical TGFβ activation, potentially identifying novel gene expressions involved in CAF activation. Additionally, optimal protein secretion conditions of confirmed CAF-upregulated genes need to be established to determine their contribution to the TME.

Keywords: cancer-associated fibroblasts; cellular communication; extracellular vesicles; lung adenocarcinoma; tumor microenvironment

DOI: https://doi.org/10.3390/biomedicines12112523