bims-meluca 2023-12-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–12–24
twelve papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Soluble PD-L1 changes in advanced non-small cell lung cancer patients treated with PD-1 inhibitors: an individual patient data meta-analysis.
PD-L1 overexpression induces STAT signaling and promotes the secretion of pro-angiogenic cytokines in non-small cell lung cancer (NSCLC).
Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial.
Impact of Different Treatment Regimens and Timeframes in the Plasmatic Metabolic Profiling of Patients with Lung Adenocarcinoma.
Prognostic value of diffuse cancer inflammation index (ALI), serum neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) in advanced-stage lung cancer.
Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway.
Clinical markers predict the efficacy of several immune checkpoint inhibitors in patients with non-small cell lung cancer in China.
Sixth-Week Immune-Nutritional-Inflammatory Biomarkers: Can They Predict Clinical Outcomes in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors?
Predictive value of metabolic parameters derived from preoperative 18F-FDG positron emission tomography/computed tomography for brain metastases in patients with surgically resected non-small cell lung cancer.
Whole stromal fibroblast signature is linked to specific chemokine and immune infiltration patterns and to improved survival in NSCLC.
Pan-cancer analysis identifies protein arginine methyltransferases PRMT1 and PRMT5 and their related signatures as markers associated with prognosis, immune profile, and therapeutic response in lung adenocarcinoma.
Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study.

Front Immunol. 2023 ;14 1308381

Soluble PD-L1 changes in advanced non-small cell lung cancer patients treated with PD-1 inhibitors: an individual patient data meta-analysis.

Takashi Shimizu, Eisuke Inoue, Ryotaro Ohkuma, Shinichi Kobayashi, Takuya Tsunoda, Satoshi Wada.

   Introduction: Currently, first-line immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1) inhibitors, are utilized as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand-1 (PD-L1) expression (≧50%). Pre-treatment or post-treatment serum soluble PD-L1 (sPD-L1) has been identified as a potential biomarker for assessing ICI efficacy through fixed-point observations. However, existing studies on sPD-L1 changes have produced inconsistent results or have had sample sizes too small to detect clinically meaningful effect sizes. To elucidate the role of sPD-L1, we conducted a collaborative individual patient data meta-analysis of PD-1 inhibitor treatments.
Methods: We conducted a thorough search of articles in PubMed via Medline, Embase, Scopus, and Cochrane databases from inception to October 20, 2023. Trials were deemed eligible if they contained individual datasets for advanced NSCLC patients, including data on overall survival (OS)/progression-free survival (PFS), as well as pre- and post-treatment sPD-L1 levels after 3-4 cycles of PD-1 inhibitor treatments. Our analysis focused on patients who completed 3-4 cycles of PD-1 inhibitor treatments. The primary outcome measure was OS/PFS, and we assessed changes in sPD-L1 concentration pre- and post-treatment through ELISA analyses.
Results: From our search, we identified a potential seven trials, encompassing 256 patients. Among these, two trials with 26 patients met the criteria for inclusion in our primary analyses. Over a median follow-up period of 10 months, pooled univariate analysis revealed that increases in sPD-L1 levels during PD-1 inhibitor treatment were not associated with OS (HR = 1.25; CI: 0.52-3.02)/PFS (HR = 1.42; CI: 0.61-3.30) when compared to cases with sPD-L1 decreases. Subgroup analyses indicated that the impact of sPD-L1 changes on overall mortality/progression-related mortality remained consistent regardless of gender, age, or the type of treatment (nivolumab or pembrolizumab).
Conclusion: Our findings suggest that changes in sPD-L1 levels during PD-1 inhibitor treatment do not significantly influence the prognosis of advanced NSCLC patients, regardless of gender, age, or treatment type. Continuous monitoring of sPD-L1 may not offer significant advantages compared to fixed-point observations.

Keywords:  PD-1 inhibitors; advanced non-small cell lung cancer; biomarker; individual patient data meta-analysis; soluble PD-L1

DOI:  https://doi.org/10.3389/fimmu.2023.1308381
Lung Cancer. 2023 Dec 12. pii: S0169-5002(23)00976-5. [Epub ahead of print]187 107438

PD-L1 overexpression induces STAT signaling and promotes the secretion of pro-angiogenic cytokines in non-small cell lung cancer (NSCLC).

A Cavazzoni, G Digiacomo, F Volta, R Alfieri, E Giovannetti, L Gnetti, L Bellini, M Galetti, C Fumarola, G Xu, M Bonelli, S La Monica, M Verzè, A Leonetti, K Eltayeb, S D'Agnelli, L Moron Dalla Tor, R Minari, P G Petronini, M Tiseo.

   BACKGROUND: Monoclonal antibodies (ICI) targeting the immune checkpoint PD-1/PD-L1 alone or in combination with chemotherapy have demonstrated relevant benefits and established new standards of care in first-line treatment for advanced non-oncogene addicted non-small cell lung cancer (NSCLC). However, a relevant percentage of NSCLC patients, even with high PD-L1 expression, did not respond to ICI, highlighting the presence of intracellular resistance mechanisms that could be dependent on high PD-L1 levels. The intracellular signaling induced by PD-L1 in tumor cells and their correlation with angiogenic signaling pathways are not yet fully elucidated.
METHODS: The intrinsic role of PD-L1 was initially checked in two PD-L1 overexpressing NSCLC cells by transcriptome profile and kinase array. The correlation of PD-L1 with VEGF, PECAM-1, and angiogenesis was evaluated in a cohort of advanced NSCLC patients. The secreted cytokines involved in tumor angiogenesis were assessed by Luminex assay and their effect on Huvec migration by a non-contact co-culture system.
RESULTS: PD-L1 overexpressing cells modulated pathways involved in tumor inflammation and JAK-STAT signaling. In NSCLC patients, PD-L1 expression was correlated with high tumor intra-vasculature. When challenged with PBMC, PD-L1 overexpressing cells produced higher levels of pro-angiogenic factors compared to parental cells, as a consequence of STAT signaling activation. This increased production of cytokines involved in tumor angiogenesis largely stimulated Huvec migration. Finally, the addition of the anti-antiangiogenic agent nintedanib significantly reduced the spread of Huvec cells when exposed to high levels of pro-angiogenic factors.
CONCLUSIONS: In this study, we reported that high PD-L1 modulates STAT signaling in the presence of PBMC and induces pro-angiogenic factor secretion. This could enforce the role of PD-L1 as a crucial regulator of the tumor microenvironment stimulating tumor progression, both as an inhibitor of T-cell activity and as a promoter of tumor angiogenesis.

Keywords:  Angiogenesis; Cell signaling; NSCLC; PD-L1; STAT

DOI:  https://doi.org/10.1016/j.lungcan.2023.107438
Nat Commun. 2023 Dec 19. 14(1): 8435

Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial.

Nasser K Altorki, Zachary H Walsh, Johannes C Melms, Jeffery L Port, Benjamin E Lee, Abu Nasar, Cathy Spinelli, Lindsay Caprio, Meri Rogava, Patricia Ho, Paul J Christos, Ashish Saxena, Olivier Elemento, Bhavneet Bhinder, Casey Ager, Amit Dipak Amin, Nicholas J Sanfilippo, Vivek Mittal, Alain C Borczuk, Sylvia C Formenti, Benjamin Izar, Timothy E McGraw.

We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1-84.5) and 65% (95% CI: 52.5-76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0-80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6-83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence.

DOI: https://doi.org/10.1038/s41467-023-44195-x
Metabolites. 2023 Nov 30. pii: 1180. [Epub ahead of print]13(12):

Impact of Different Treatment Regimens and Timeframes in the Plasmatic Metabolic Profiling of Patients with Lung Adenocarcinoma.

Daniela Madama, David F Carrageta, Bárbara Guerra-Carvalho, Maria F Botelho, Pedro F Oliveira, Carlos R Cordeiro, Marco G Alves, Ana M Abrantes.

  In recent years, the treatment of advanced non-small cell lung cancer (NSCLC) has suffered a variety of alterations. Chemotherapy (CTX), immunotherapy (IT) and tyrosine kinase inhibitors (TKI) have shown remarkable results. However, not all patients with NSCLC respond to these drug treatments or receive durable benefits. In this framework, metabolomics has been applied to improve the diagnosis, treatment, and prognosis of lung cancer and particularly lung adenocarcinoma (AdC). In our study, metabolomics was used to analyze plasma samples from 18 patients with AdC treated with CTX or IT via 1H-NMR spectroscopy. Relevant clinical information was gathered, and several biochemical parameters were also evaluated throughout the treatments. During the follow-up of patients undergoing CTX or IT, imaging control is recommended in order to assess the effectiveness of the therapy. This evaluation is usually performed every three treatments. Based on this procedure, all the samples were collected before the beginning of the treatment and after three and six treatments. The identified and quantified metabolites in the analyzed plasma samples were the following: isoleucine, valine, alanine, acetate, lactate, glucose, tyrosine, and formate. Multivariate/univariate statistical analyses were performed. Our data are in accordance with previous published results, suggesting that the plasma glucose levels of patients under CTX become higher throughout the course of treatment, which we hypothesize could be related to the tumor response to the therapy. It was also found that alanine levels become lower during treatment with CTX regimens, a fact that could be associated with frailty. NMR spectra of long responders' profiles also showed similar results. Based on the results of the study, metabolomics can represent a potential option for future studies, in order to facilitate patient selection and the monitoring of therapy efficacy in treated patients with AdC. Further studies are needed to improve the prospective identification of predictive markers, particularly glucose and alanine levels, as well as confer guidance to NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.

Keywords:  chemotherapy; immunotherapy; lung adenocarcinoma; metabolomics

DOI:  https://doi.org/10.3390/metabo13121180
J Cancer Res Ther. 2023 Dec 15.

Prognostic value of diffuse cancer inflammation index (ALI), serum neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) in advanced-stage lung cancer.

Aysen Evkan Ozturk, Berna Komurcuoglu, Gamze Kaplan Karakurt, Ozgur Ozturk.

INTRODUCTION: Lung cancer is the most common type of cancer that causes death worldwide. Systemic inflammation has been shown to play a role in cancer etiopathogenesis and can be activated from oncogenic changes in cancer cells. In our study, the prognostic effects of inflammatory parameters calculated from serum were investigated in lung cancer.
METHOD: One hundred fifteen patients with locally advanced and advanced lung cancer who were diagnosed in our chest diseases clinic between 2013 and 2015 were retrospectively analyzed. The relationship between advanced lung cancer inflammation index (ALI index), serum neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) levels at the time of diagnosis were calculated, and their relationship with overall survival (OS), disease-free survival, and the treatment response and their effect on predicting prognosis were investigated.
FINDINGS: When the ALI value was examined in the group with non-small cell lung, the OS was found to be 9.018 months in the group over 18 years of age and it was 3.78 months in the group below. Low ALI index was significantly associated with short survival (P <.05). When the NLR values were examined in the entire patient group, OS more than 5 was 5.95 months and less than 9.63 months. A high NLR value was significantly associated with short survival (P <.05). No significant relationships were detected between PLR and OS. When the determined cut-off values were used, no significant correlation was found between NLR, ALI, and PLR levels and progression-free survival (P >.05).
CONCLUSION: In our study, it was concluded that elevated NLR levels and low ALI values at the time of diagnosis of advanced-stage lung cancer were associated with poor survival, and those values may be useful in predicting survival and prognosis when the cut-off values were used. These parameters can be useful in routine use because they can be easily calculated without additional costs.

DOI: https://doi.org/10.4103/jcrt.JCRT_1762_20
Oncol Rep. 2024 Feb;pii: 29. [Epub ahead of print]51(2):

Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway.

Fenglin Zhang, Yan Qi, Jing Li, Boyang Liu, Zhonghui Liu, Xueling Cui.

  Activin A, a member of the transforming growth factor‑β (TGF‑β) superfamily, has been implicated in the tumorigenesis and progression of various cancers. However, it remains unclear whether activin A induces apoptosis in human lung adenocarcinoma cells through the endoplasmic reticulum (ER) stress pathway. In the present study, BrdU, flow cytometry and western blotting were used to examine cell proliferation, apoptosis and protein expression, respectively. The present study revealed that activin A inhibited human lung adenocarcinoma A549 cell proliferation, induced apoptosis, and upregulated the protein levels of C/EBP homologous protein (CHOP), growth arrest and DNA damage‑inducible protein 34 (GADD34), cleaved‑caspase‑3 and caspase‑12. Furthermore, the administration of activin A did not alter the levels of suppressor of mothers against decapentaplegic 3 (Smad3) or phosphorylated (p)‑Smad3 proteins, whereas, it significantly elevated the levels of ActRIIA and p‑extracellular signal regulated kinase proteins 1 and 2 (ERK1/2) proteins in A549 cells. The apoptotic effects of activin A on A549 cells were attenuated by the ERK inhibitor FR180204, which also downregulated CHOP and caspase‑12 protein levels. Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTA‑AM) inhibited activin A‑induced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIA‑ERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.

Keywords:  ActRIIA‑ERK1/2 signaling; Ca2+ signaling; activin A; apoptosis; endoplasmic reticulum stress; lung adenocarcinoma

DOI:  https://doi.org/10.3892/or.2023.8688
Front Immunol. 2023 ;14 1276107

Clinical markers predict the efficacy of several immune checkpoint inhibitors in patients with non-small cell lung cancer in China.

Yuxin Wang, Jiahui Lu, Chenxi Wu, Fei Fei, Zhuze Chu, Peihua Lu.

   Objectives: Immune checkpoint inhibitors (ICIs) are one of the most significant oncological treatment modalities as a result of the rapid advancement of immunotherapy. Programmed Cell Death-Ligand 1 (PD-L1) and tumor mutational burden (TMB) have emerged as key markers for predicting the efficacy and prognosis of ICIs in non-small cell lung cancer (NSCLC), and the predictive role of tumor-infiltrating lymphocytes (TILs) has also received significant attention. However, the prognosis of some individuals cannot be determined by these indicators; for instance, some patients with low PD-L1 expression also benefit from longer survival. Therefore, the purpose of this research was to investigate the connection between new haematological and pathological markers and clinical outcomes in NSCLC patients receiving ICIs.
Methods: Seventy-six patients with stage III-IV NSCLC treated with ICIs were included in this study. We used the Mann-Whitney test, COX regression and Kaplan-Meier analysis to retrospectively analyze peripheral blood indicators and survival prognostic data of 76 patients in order to investigate the relationship between baseline neutrophil-to-lymphocyte ratio (NLR) and the efficacy of ICIs. To investigate the correlation between CXCL13, CXCR5, CD8 and the efficacy of ICIs, we assessed the expression levels of aforementioned indicators in biopsied tissues of 10 non-small cell lung tumors by immunohistochemistry (IHC) and immunofluorescence (IF) and performed statistical analysis.
Results: Disease control rate (DCR) was higher in patients with baseline NLR <3.4 (p=0.016) and neutrophil percentage <71% (P=0.015). Baseline NLR (HR=2.364, P=0.003) and neutrophil percentage (HR=2.824, P=0.013) had the greatest influence on patients' survival prognosis, with baseline NLR exhibiting a stronger predictive value (AUC=0.717), according to univariate and multifactorial COX regression analyses of progression-free survival (PFS) and overall survival (OS). In NSCLC tissues, higher expression of CXCL13 was associated with better clinical outcomes (P=0.032) and higher expression of CD8 was associated with prolonged survival (P=0.022).
Conclusion: Low baseline NLR in peripheral blood and high expression of CD8 in tissues are associated with longer PFS and may have a potential predictive value for patients with stage III-IV NSCLC using ICIs.

Keywords:  CD8; CXCL13; biomarker; immune checkpoint inhibitors; neutrophil-to-lymphocyte ratio; non-small cell lung cancer; prognostic value

DOI:  https://doi.org/10.3389/fimmu.2023.1276107
Curr Oncol. 2023 Dec 18. 30(12): 10539-10549

Sixth-Week Immune-Nutritional-Inflammatory Biomarkers: Can They Predict Clinical Outcomes in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors?

Polat Olgun, Omer Diker.

   BACKGROUND: We investigated the relationships between inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), Lung Immune Prognostic Index (LIPI), and modified Glasgow prognostic score (mGPS) to determine whether they could predict treatment response to pembrolizumab or nivolumab (immunotherapy) 6 weeks after the start of treatment (post-treatment).
METHODS: We included all patients with lung cancer treated with immunotherapy. We examined the biomarker trends and explored their associations with progression-free survival (PFS), overall survival (OS), and response rate (RR) at 6 weeks.
RESULTS: Eighty-three patients were enrolled in the study. The presence of liver metastasis, low post-treatment NLR (<5), low post-treatment PLR (<170), intermediate post-treatment LIPI, and immune-related adverse events were significantly associated with the response. The multivariate analysis revealed that high post-treatment NLRs ≥ 5 (p = 0.004) and PLRs ≥ 170 (p ≤ 0.001) were independent prognostic factors of shorter OS. A good LIPI status was associated with better PFS (p = 0.020) and OS (p = 0.065). Post-treatment mGPS (0-2) was significantly associated with improved PFS (p = 0.009) and OS (p = 0.064).
CONCLUSIONS: Post-treatment NLR, PLR, LIPI, and mGPS are associated with worse OS and recurrence. These findings should be independently and prospectively validated in further studies.

Keywords:  Lung Immune Prognostic Index (LIPI); immune-based prognostic scores; modified Glasgow prognostic score (mGPS); neutrophil-to-lymphocyte ratio (NLR); platelet-to-lymphocyte ratio (PLR)

DOI:  https://doi.org/10.3390/curroncol30120769
Quant Imaging Med Surg. 2023 Dec 01. 13(12): 8545-8556

Predictive value of metabolic parameters derived from preoperative 18F-FDG positron emission tomography/computed tomography for brain metastases in patients with surgically resected non-small cell lung cancer.

Jingjie Shang, Yongjin Tang, Bingyu Ran, Biao Wu, Yingxin Li, Yong Cheng, Bin Guo, Jian Gong, Lu Wang, Xueying Ling, Hao Xu.

   Background: Brain metastases (BMs) are common complications in patients with non-small cell lung cancer (NSCLC). The purpose of this study was to investigate whether the metabolic parameters derived from preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) can predict BM development in patients with surgically resected NSCLC.
Methods: We retrospectively reviewed 128 consecutive patients with stage I-IIIA NSCLC who underwent 18F-FDG PET/CT before curative surgery at The First Affiliated Hospital of Jinan University between November 2012 and October 2021. By drawing a volume of interest (VOI), the maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor as well as the mean SUV (SUVmean) of the liver and arterial blood were measured. The tumor-to-liver SUV ratio (TLR) and tumor-to-blood SUV ratio (TBR) were also calculated. Receiver operating characteristic curve analysis was used to determine the best cut-off values for positron emission tomography (PET) parameters to predict BM-free survival, and Cox proportional hazards regression analysis was used to assess the predictive value of clinical variables and PET parameters.
Results: The median follow-up duration for survival patients was 23.4 months, and 15 patients (11.7%) experienced BM as the initial relapse site. The cumulative rates of BM over the course of 1, 2, and 5 years were 4.5%, 10.5%, and 17.5%, respectively. The optimal cut-off values for the prediction of BM-free survival were 7.7, 4.9, and 4.5 for SUVmax, TLR, and TBR, and 5.5 mL and 16.1 for MTV and TLG, respectively. In the Cox proportional hazards model, the risk of BM was significantly associated with TLR [hazard ratio (HR) =10.712; 95% confidence interval (CI): 2.958-38.801; P<0.001] and MTV (HR =3.150; 95% CI: 0.964-10.293; P=0.020) after adjusting for tumor stage, clinicopathological factors, and other PET parameters.
Conclusions: Preoperative TLR and MTV of the primary tumor may be helpful in predicting BM development in patients with surgically resected NSCLC. Tumor metabolic parameters may potentially be used to stratify the risk of BM and determine individualized surveillance strategies.

Keywords:  18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT); brain metastases (BMs); metabolic parameters; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.21037/qims-23-385
Oncoimmunology. 2023 ;12(1): 2274130

Whole stromal fibroblast signature is linked to specific chemokine and immune infiltration patterns and to improved survival in NSCLC.

Stefan Koeck, Arno Amann, Johan Kern, Marit Zwierzina, Edith Lorenz, Sieghart Sopper, Heinz Zwierzina, Finn Mildner, Martina Sykora, Susanne Sprung, Hubert Hackl, Florian Augustin, Hubert T Maier, Andreas Pircher, Georg Pall, Dominik Wolf, Gabriele Gamerith.

  Cancer associated fibroblasts (CAF) are known to orchestrate multiple components of the tumor microenvironment, whereas the influence of the whole stromal-fibroblast compartment is less understood. Here, an extended stromal fibroblast signature was investigated to define its impact on immune cell infiltration. The lung cancer adenocarcinoma (LUAD) data set of the cancer genome atlas (TCGA) was used to test whole stroma signatures and cancer-associated fibroblast signatures for their impact on prognosis. 3D cell cultures of the NSCLC cancer cell line A549 together with the fibroblast cell line SV80 were used in combination with infiltrating peripheral blood mononuclear cells (PBMC) for in-vitro investigations. Immune cell infiltration was assessed via flow cytometry, chemokines were analyzed by immunoassays and RNA microarrays. Results were confirmed in specimens from NSCLC patients by flow cytometry or immunohistochemistry as well as in the TCGA data set. The TCGA analyses correlated the whole stromal-fibroblast signature with an improved outcome, whereas no effect was found for the CAF signatures. In 3D microtumors, the presence of fibroblasts induced infiltration of B cells and CD69+CD4+ T cells, which was linked to an increased expression of CCL13 and CXCL16. The stroma/lymphocyte interaction was confirmed in NSCLC patients, as stroma-rich tumors displayed an elevated B cell count and survival in the local cohort and the TCGA data set. A whole stromal fibroblast signature was associated with an improved clinical outcome in lung adenocarcinoma and in vitro and in vivo experiments suggest that this signature increases B and T cell recruitment via induction of chemokines.

Keywords:  CAF; cancer; co-culture; immune cells; infiltration; microenvironment

DOI:  https://doi.org/10.1080/2162402X.2023.2274130
Heliyon. 2023 Dec;9(12): e22088

Pan-cancer analysis identifies protein arginine methyltransferases PRMT1 and PRMT5 and their related signatures as markers associated with prognosis, immune profile, and therapeutic response in lung adenocarcinoma.

Jia Wang, Meng Wu, Jujie Sun, Minxin Chen, Zengfu Zhang, Jinming Yu, Dawei Chen.

   Purpose: Protein arginine methyltransferases (PRMTs) regulate several signal transduction pathways involved in cancer progression. Recently, it has been reported that PRMTs are closely related to anti-tumor immunity; however, the underlying mechanisms have yet to be studied in lung adenocarcinoma (LUAD). In this study, we focused on PRMT1 and PRMT5, key members of the PRMT family. And their signatures in lung carcinoma associated with prognosis, immune profile, and therapeutic response including immunotherapy and radiotherapy were explored.
Methods: To understand the function of PRMT1 and PRMT5 in tumor cells, we examined the association between the expression of PRMT1 and PRMT5 and the clinical, genomic, and immune characteristics, as well as the sensitivity to immunotherapy and radiotherapy. Specifically, our investigation focused on the role of PRMT1 and PRMT5 in tumor progression, with particular emphasis on interferon-stimulated genes (ISGs) and the pathway of type I interferon. Furthermore, the influence of proliferation, migration, and invasion ability was investigated based on the expression of PRMT1 and PRMT5 in human lung adenocarcinoma cell lines.
Results: Through the examination of receiver operating characteristic (ROC) and survival studies, PRMT1 and PRMT5 were identified as potential biomarkers for the diagnosis and prognosis. Additionally, heightened expression of PRMT1 or PRMT5 was associated with immunosuppressive microenvironments. Furthermore, a positive correlation was observed between the presence of PRMT1 or PRMT5 with microsatellite instability, tumor mutational burden, and neoantigens in the majority of cancers. Moreover, the predictive potential of PRMT1 or PRMT5 in individuals undergoing immunotherapy has been acknowledged. Our study ultimately revealed that the inhibition of PRMT1 and PRMT5 in lung adenocarcinoma resulted in the activation of the cGAS-STING pathway, especially after radiation. Favorable prognosis was observed in lung adenocarcinoma patients receiving radiotherapy with reduced PRMT1 or PRMT5 expression. It was also found that the expression of PRMT1 and PRMT5 influenced proliferation, migration, and invasion of human lung adenocarcinoma cell lines.
Conclusion: The findings indicate that PRMT1 and PRMT5 exhibit potential as immune-related biomarkers for the diagnosis and prognosis of cancer. Furthermore, these biomarkers could be therapeutically targeted to augment the efficacy of immunotherapy and radiotherapy in lung adenocarcinoma.

Keywords:  PRMT1; PRMT5; Prognosis; Radiotherapy; Tumor immune microenvironment; Type I interferon pathway

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22088
BMC Cancer. 2023 Dec 16. 23(1): 1244

Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study.

Xinlong Zheng, Longfeng Zhang, Lin Wu, Jun Zhao, Jianguo Sun, Yong Fang, Jin Zhou, Qian Chu, Yihong Shen, Zhenzhou Yang, Lijin Chen, Meijuan Huang, Xiaoyan Lin, Zhenhua Liu, Peng Shen, Zhijie Wang, Xin Wang, Huijuan Wang, Zhengbo Han, Anwen Liu, Hongmei Zhang, Feng Ye, Wen Gao, Fang Wu, Zhengbo Song, Shengchi Chen, Chenzhi Zhou, Qian Wang, Chunwei Xu, Dingzhi Huang, Xiaobin Zheng, Qian Miao, Kan Jiang, Yiquan Xu, Shiwen Wu, Haibo Wang, Qiuyu Zhang, Shanshan Yang, Yujing Li, Sihui Chen, Gen Lin.

   AIMS: To investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC).
MATERIALS AND METHODS: In this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups.
RESULTS: Of the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12-2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13-4.44; p = 0.033).
CONCLUSION: In patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.

Keywords:  C-reactive protein; Immune checkpoint inhibitors; Lung squamous cell carcinoma; Predictive biomarker

DOI:  https://doi.org/10.1186/s12885-023-11737-x