bims-tuinly 2025-08-24 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–08–24
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Autologous Tumor-Infiltrating Lymphocyte Infusion plus Anti-Programmed Cell Death Protein 1 Therapy to Cure Advanced Hepatocellular Carcinoma following Palliative Hepatectomy.
Adoptive cell therapy for cancer: combination strategies and biomarkers.
Association of TILs and HER2-low status with pathological response in triple-negative breast cancer.
Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00.
Development and validation of a gradient boosting machine-based model for predicting tumor-infiltrating lymphocyte proportions in breast cancer.
Inhibition of ATM enhances the immunogenicity of triple-negative breast cancer by promoting MHC-I expression.
Cytotoxic CD8+ T Cells Downregulate GPX4 to Promote Ferroptosis in Melanoma that Drives Antitumor Immunity.
In vivo production of CAR T cell: Opportunities and challenges.
ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images.
Prognostic value of positive lymph node ratio, tumor deposit, and perineural invasion in advanced colorectal signet-ring cell carcinoma.
Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8 + T cells underlies distinct functional potential.
Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity.
Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma.

Liver Cancer. 2025 Aug;14(4): 497-505

Autologous Tumor-Infiltrating Lymphocyte Infusion plus Anti-Programmed Cell Death Protein 1 Therapy to Cure Advanced Hepatocellular Carcinoma following Palliative Hepatectomy.

Tian Xia, Tong Yuan, Li-Jun Chen, Chang-Li Wang, Er-Lei Zhang, Bin-Yong Liang, Zun-Yi Zhang, Ming-Wei Wang, Xiao-Ping Chen, Zhi-Yong Huang.

   Introduction: Adoptive cell therapy derived from autologous tumor-infiltrating lymphocytes (TILs) has demonstrated promising therapeutic efficacy in several cancers. However, its possible synergistic effects with anti-PD-1 therapy in advanced hepatocellular carcinoma (aHCC) remain unexplored. This study aimed to investigate the efficacy of TIL infusion combined with anti-PD-1 therapy for aHCC.
Case Presentation: Referring to the current protocol of our clinical trial (NCT03658785), 2 patients with HCC at BCLC stage C were enrolled to receive autologous TIL infusion combined with anti-PD-1 therapy. They underwent unplanned palliative tumor resection to alleviate pain caused by tumor rupture prior to receiving TIL infusion plus anti-PD-1 therapy. Long-term outcomes and treatment-related adverse events were evaluated. Throughout the entire treatment process, both patients experienced only mild symptoms. Notably, both patients achieved complete responses to the treatment and have remained tumor-free for 2 and 4 years, respectively.
Conclusion: Autologous TIL infusion combined with anti-PD-1 therapy is a safe and feasible strategy for patients with aHCC. Palliative hepatectomy with maximal tumor burden reduction may significantly improve its efficacy and even results in cure for aHCC patients.

Keywords:  Adoptive cell therapy; Advanced hepatocellular carcinoma; Anti-PD-1 therapy; Palliative hepatectomy; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1159/000544163
Front Immunol. 2025 ;16 1603792

Adoptive cell therapy for cancer: combination strategies and biomarkers.

Shiyu Liu, Weibo Jiang, Jiyao Sheng, Lixuan Wang, Mengying Cui.

  Adoptive cell therapy (ACT) is a therapeutic approach that involves the isolation, modification, and expansion of immune cells ex vivo, followed by their reinfusion into the patient to enhance anti-tumor immune responses. Various forms of ACT have demonstrated promising clinical outcomes across multiple types of cancer. For example, chimeric antigen receptor (CAR)-T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, and T-cell receptor-engineered T cell (TCR-T) therapy have received approval from the US Food and Drug Administration. However, the clinical application of ACT remains constrained by limited efficacy and potentially life-threatening toxicities. Diminished efficacy may result from an immunosuppressive tumor microenvironment, poor trafficking and infiltration, exhaustion of infused cells, tumor heterogeneity, and antigen escape. To address these challenges, combination strategies have been developed with the goals of enhancing efficacy and managing adverse effects. Conventional treatments and non-ACT forms of immunotherapy have been incorporated into these combination approaches. Biomarkers play an essential role in optimizing ACT strategies and addressing associated complexities. They can aid in candidate selection, assess the quality of ACT products, monitor long-term therapeutic efficacy, manage toxicity, and guide combination regimens. This review briefly outlines six ACT modalities and their common limitations, summarizes current combination strategies, explores potential future regimens, and offers an overview of biomarkers relevant to ACT. These insights provide valuable guidance for the development and clinical implementation of more effective ACT-based therapies, ultimately aiming to improve patient outcomes.

Keywords:  CAR-T cells; TCR-T cells; TILs; adoptive cell therapy; biomarkers; combination therapy; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1603792
Medicine (Baltimore). 2025 Aug 15. 104(33): e43971

Association of TILs and HER2-low status with pathological response in triple-negative breast cancer.

İlknur Deliktaş Onur, Didem Kurukafa, Yeşim Ağyol, Hatice Gülgün Firat, Elif Sertesen Çamöz, Alper Türkel, Berkan Karabuğa, Sibel Yenidünya, İbrahim Vedat Bayoğlu, Öztürk Ateş.

  Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the lowest treatment success rate. The aim of this study is to determine the relationship between tumor-infiltrating lymphocytes (TILs) score and HER2 score in TNBC patients receiving neoadjuvant chemotherapy and its effectiveness in predicting treatment response. One hundred two patients diagnosed with TNBC, who received neoadjuvant chemotherapy and underwent surgery were included in the study. The TILs score in the tru-cut biopsies of the patients was evaluated, and pathological response rates from mastectomy materials were also examined. The pathological complete response (pCR) was observed after neoadjuvant chemotherapy in 43 (43.2%) patients, while no pCR in 58 (56.8%) patients. Chi-square analysis revealed a significant relationship between the TILs score (p: 0.001), clinical T stage (P = .019), and pCR response. In multivariate logistic regression analysis, a significant relationship was found only between TILs and pCR (OR = 13.3, 95% CI = 2.23-81.23, P = .00). No significant relationship was found between pCR and HER2 score (P = .23), Ki-67 (P = .52), grade (P = .87) and menopausal status (P = .20). No significant relationship was found in the correlation analysis between TILs and HER2 score (P = .26, CC = 0.14). TILs score in TNBC is related to both the pCR and disease prognosis. We believe that larger-scale studies are needed to identify more factors that may predict neoadjuvant treatment response in TNBC patients. Additionally, we suggest that the relationship between HER2 score and TILs score in TNBC patients should be examined in larger studies.

Keywords:  HER2 low breast cancer; HER2 zero breast cancer; TILs; pathological complete response; triple-negative breast cancer; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1097/MD.0000000000043971
iScience. 2025 Aug 15. 28(8): 112964

Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00.

Andrea Joaquin Garcia, Takashi Semba, Mattia Rediti, Daniel J McGrail, Xuemei Xie, Xiaoping Wang, Dileep R Rampa, David Venet, Laurence Buisseret, Samira Majjaj, Roswitha Kammler, Marco Colleoni, Sherene Loi, Giuseppe Viale, Meredith M Regan, Françoise Rothé, Christos Sotiriou, Naoto T Ueno.

  Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8+/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies.

Keywords:  Cancer; Immunology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112964
Am J Transl Res. 2025 ;17(7): 5586-5601

Development and validation of a gradient boosting machine-based model for predicting tumor-infiltrating lymphocyte proportions in breast cancer.

Xiaobin Zhang, Shulin Xian, Daolai Huang, Naihan Cui, Jiehua Li.

   OBJECTIVE: To construct and validate a multidimensional model for evaluating tumor-infiltrating lymphocyte (TIL) levels in breast cancer (BC) patients.
METHODS: This retrospective study included 318 BC patients with 318 lesions confirmed by MRI and surgical pathology in the First Affiliated Hospital of Guangxi Medical University from January 2021 to December 2024. The patients were randomly split into a training set (n=228) and a validation (n=90) set, and further divided into low and high TIL groups based on immunophenotype assessment. Multivariate Logistic regression was used to identify independent predictors of TILs levels. A gradient boosting machine (GBM) model and a Logistic regression model were built. Model performance was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). An external validation cohort of 120 BC patients admitted between January 2025 and May 2025 was used to verify the predictive accuracy of the GBM model. Results Ki-67 level, internal enhancement pattern, multifocality, apparent diffusion coefficient (ADC) value, and neutrophil-to-lymphocyte ratio (NLR) were identified as independent predictors of high TIL levels. The GBM model demonstrated superior performance compared to the Logistic regression in the training set (AUC: 0.859 vs 0.724; P=0.014). Calibration curves indicated good agreement between predicted and observed probabilities in both models. DCA showed that the GBM model provided higher clinical utility. External validation yielded an AUC of 0.784 for the GBM model, with the calibration curve and DCA further confirming the model's good calibration and clinical applicability.
CONCLUSION: The GBM-based multidimensional model reliably predicts TIL levels in BC patients, supporting prognosis evaluation and guiding personalized treatment strategies.

Keywords:  Breast cancer; evaluation model; multidimensional indicators; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.62347/PDEW5000
Cell Death Dis. 2025 Aug 18. 16(1): 624

Inhibition of ATM enhances the immunogenicity of triple-negative breast cancer by promoting MHC-I expression.

Jiazhen Li, Chenying Liu, Xiaolong Qian, Xiaozi Wang, Hui Sun, Lu Wang, Huiqin Xue, Yuanming Song, Jiamei Liu, Yafang Zhao, Yumian Jia, Fengxia Qin, Tianhua Zhang, Xiaojing Guo.

The immunotherapy has achieved some efficacy in triple-negative breast cancer (TNBC), but the benefit population is limited, primarily due to an abnormal immune microenvironment. Thus, it is necessary to explore new molecular targets to enhance the immunogenicity of TNBC cells and improve their responsiveness to immunotherapy. We found that a key component of the DNA repair system, Ataxia telangiectasia mutated (ATM), may function as an immune response inhibitor. In this study, the inverse correlation between ATM and CD8+ T cells and tumor-infiltrating lymphocytes (TILs) was confirmed by immunochemical staining of 191 TNBC specimens. Subsequently, inhibition of ATM increased the expression of major histocompatibility complex I (MHC-I) and enhanced the infiltration and cytotoxic activity of CD8+ T cells by Western blot and flow cytometry analysis. In addition, we further confirmed that the MHC-I upregulation induced by ATM inhibition depends on the activation of the c-Jun/TNF-α/p-STAT1 pathway. Animal studies have shown that ATM deficiency delays tumor growth and sensitizes tumors to PD-1 blockade and radiotherapy. This study reveals a new mechanism by which ATM negatively regulates MHC-I by inhibiting the c-Jun/TNF-α/p-STAT1 pathway in TNBC, and shows an important role in mediating CD8+ T cells infiltration and regulating the "heat" of the immune microenvironment. The combination of ATM inhibitors with radiotherapy and Immune-checkpoint blockade (ICB) therapies may be a new strategy for TNBC treatment.

DOI: https://doi.org/10.1038/s41419-025-07944-y
Cancer Res. 2025 Aug 19.

Cytotoxic CD8+ T Cells Downregulate GPX4 to Promote Ferroptosis in Melanoma that Drives Antitumor Immunity.

Karine Flem-Karlsen, Ronan Talty, Meaghan K McGeary, Koonam Park, Durga Thakral, Veronica T Brooks, Andrew J Daniels, William Damsky, Simon F Roy, Goran Micevic, Marcus Bosenberg.

Identifying factors that mediate successful anticancer immune responses is necessary to improve outcomes for patients with advanced cancers. Here, we performed single-cell RNA sequencing on mouse melanomas experiencing successful and unsuccessful immune responses and discovered a prominent ferroptosis signature in tumors undergoing immune-mediated regression. Pairing ferroptosis inducers and inhibitors with immunotherapies ex vivo and in vivo highlighted a central role for ferroptosis in stimulating the anti-melanoma immune response. In co-culture models, CD8+ T cells drove melanoma cell ferroptosis by altering the expression of glutathione peroxidase 4 (GPX4), a crucial antioxidant enzyme known for its role in preventing lipid peroxidation. Direct contact between tumor cells and CD8+ T cells was needed to sustain GPX4 downregulation over time, resulting in ferroptotic cell death. Finally, single-cell RNA sequencing data from human melanoma tumors responding to immunotherapy revealed a ferroptosis signature that mirrors the mouse model. Together, these results offer crucial insights into the role of ferroptosis in antitumor immunity and highlight the potential of modulating ferroptosis to enhance immunotherapy responses.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1952
Genes Dis. 2025 Nov;12(6): 101612

In vivo production of CAR T cell: Opportunities and challenges.

Zhiqiang Song, Yi Zhou, Binbin Wang, Yuke Geng, Gusheng Tang, Yang Wang, Jianmin Yang.

  Chimeric antigen receptor T (CAR T) cell therapy has achieved remarkable efficacy for patients with hematological malignancies. However, in vitro viral vector-mediated production of CAR T cells is time-consuming and expensive and impairs T cell function. On one hand, an elaborate manufacturing process not only impairs the function of CAR T cells but also limits its usage in patients with rapidly progressing diseases. On the other hand, high costs are incompatible with broad clinical applications for sizable populations. In vivo production of CAR T cells is a novel approach that can avoid complicated production processes and reduce costs through mass production. Additionally, in vivo production of CAR T cells does not damage the function of T cells compared with in vitro production. Early studies have demonstrated promising antitumor activity of in vivo CAR T cell therapy in preclinical models of hematological malignancies. In this review, we describe the latest developments of in vivo CAR T cell therapy and discuss its potential challenges for clinical application.

Keywords:  Chimeric antigen receptor T cell; Hematological malignancies; In vivo production; Nonviral vector; Viral vector

DOI:  https://doi.org/10.1016/j.gendis.2025.101612
Nat Commun. 2025 Aug 16. 16(1): 7633

ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images.

Eric Wu, Matthew Bieniosek, Zhenqin Wu, Nitya Thakkar, Gregory W Charville, Ahmad Makky, Christian M Schürch, Jeroen R Huyghe, Ulrike Peters, Christopher I Li, Li Li, Hannah Giba, Vivek Behera, Arjun Raman, Alexandro E Trevino, Aaron T Mayer, James Zou.

Hematoxylin and eosin (H&E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we present ROSIE, a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&E images. Our model is trained on a dataset of over 1300 paired and aligned H&E and multiplex immunofluorescence (mIF) samples from over a dozen tissues and disease conditions, spanning over 16 million cells. Validation of our in silico mIF staining method on held-out H&E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&E staining alone. Additionally, ROSIE facilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.

DOI: https://doi.org/10.1038/s41467-025-62346-0
Front Mol Biosci. 2025 ;12 1617787

Prognostic value of positive lymph node ratio, tumor deposit, and perineural invasion in advanced colorectal signet-ring cell carcinoma.

Liang Chu, Han Wang, Tao Ling, Shuhan Feng, Yucheng Ding, Yan Zhang, Ying Pan, Cenzhu Wang, Xiaohong Wang, Lei Liu.

   Background: The aim of this study was to assess the prognostic significance of positive lymph node ratio (LNR), tumor deposits (TD), and perineural invasion (PNI) in advanced colorectal signet-ring cell carcinoma (SRCC).
Methods: A multicenter retrospective cohort analysis was conducted involving 677 patients with advanced colorectal SRCC. The associations of variables with CSS and OS were analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards models. A nomogram model was developed to predict outcomes.
Results: High-LNR, TD-positive, and PNI-positive were associated with poorer CSS and OS in both the training and validation cohorts. Multivariate Cox analysis identified T stage, M stage, TD, CEA, chemotherapy, and LNR as independent prognostic factors. A prognostic nomogram model incorporating these variables demonstrated excellent calibration and satisfactory predictive accuracy. Survival curves generated from individualized nomogram scores effectively discriminated prognostic outcomes (P < 0.001). The combined variable of LNR, TD, and PNI significantly enhanced the predictive performance. Specifically, the combined variable exhibited the highest relative contribution to OS at 23.4%, surpassing that of T and M stages. For CSS, its relative contribution was 21.4%, ranking second only to T and M stages.
Conclusion: LNR, TD, and PNI served as prognostic factors for advanced colorectal SRCC. The combined analysis demonstrated a higher prognostic predictive value.

Keywords:  colorectal signet ring cell carcinoma; lymph node ratio; perineural invasion; prognosis; tumor deposit

DOI:  https://doi.org/10.3389/fmolb.2025.1617787
bioRxiv. 2025 Aug 11. pii: 2025.08.08.669213. [Epub ahead of print]

Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8 + T cells underlies distinct functional potential.

Simone L Park, Mark M Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A Sullivan, Divij Mathew, Leonel Torres, Yinghui J Huang, David B Reeg, Naomi R Douek, Trenton Campos, Max Klapholz, Maria A Cardenas, Victoria Fang, Shin Foong Ngiow, K C Wumesh, Rishi R Goel, Amy E Baxter, Jennifer E Wu, Melody Tan, Corbett T Berry, Christoph T Ellebrecht, Alexander C Huang, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M Brody, Erica R Thaler, Devraj Basu, Ahmed Diab, Josephine R Giles, E John Wherry.

Persistent antigen stimulation promotes differentiation of exhausted CD8 + T (T EX ) cells. T EX cells are distinct from circulating memory T (T CIRCM ) cells but share many features with tissue-resident memory (T RM ) cells established following infection resolution. CD8 + T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T RM or T EX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T EX (TR-T EX ) cells that are ontologically and functionally distinct from T RM cells generated after antigen clearance. TR-T EX phenotypically resembled T RM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T EX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T RM cells after antigen withdrawal. Conversely, T RM cells were able to differentiate into T EX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T EX cells with patient responses to immune checkpoint blockade, and only TR-T EX but not T RM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T EX and T RM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.

DOI: https://doi.org/10.1101/2025.08.08.669213
Cancer Immunol Immunother. 2025 Aug 19. 74(9): 289

Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity.

Yoichiro Narikawa, Atsuo Kuramasu, Masahiro Hosonuma, Masakazu Murayama, Eiji Funayama, Akiko Sasaki, Yuta Baba, Hitoshi Toyoda, Junya Isobe, Kohei Tajima, Rie Nakashima, Aya Sasaki, Yuki Maruyama, Yoshitaka Yamazaki, Midori Shida, Toshiaki Tsurui, Yuya Hirasawa, Hirotsugu Ariizumi, Tomoyuki Ishiguro, Risako Suzuki, Ryotaro Ohkuma, Yutaro Kubota, Takehiko Sambe, Mayumi Tsuji, Satoshi Wada, Atsushi Horiike, Shinichi Kobayashi, Takuya Tsunoda, Sei Kobayashi, Hitome Kobayashi, Tatsunori Oguchi, Toshikazu Shimane, Yuji Kiuchi, Kiyoshi Yoshimura.

  Inosine, a bacterial metabolite and agonist of the adenosine A2A receptor, modulates antitumor immunity. However, its precise effects on immune checkpoint inhibitors remain unclear. This study aimed to evaluate the impact of inosine on the efficacy of anti-programmed cell death protein 1 (PD-1) therapy and explore strategies to counteract any potential inhibitory effects. In in vitro co-culture systems, inosine selectively suppressed cancer cell growth without impairing T-cell viability. In a murine subcutaneous tumor model, inosine treatment reduced tumor growth and was associated with elevated interferon-gamma levels in the tumor microenvironment, along with increased infiltration by tumor-infiltrating lymphocytes and enhanced splenic CD4⁺ and CD8⁺ T-cell frequencies. However, the combination of inosine with anti-PD-1 therapy attenuated the antitumor effect and increased cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in splenic T cells compared to levels after anti-PD-1 monotherapy. To overcome this inhibitory effect, we tested whether adding an anti-CTLA-4 antibody could restore antitumor immunity. Notably, the combination of inosine with both anti-PD-1 and anti-CTLA-4 antibodies significantly enhanced antitumor efficacy. These findings suggest that inosine may synergize with dual ICI therapy and represent a promising adjunct to improve immunotherapeutic outcomes.

Keywords:  CTLA-4; Immune checkpoint inhibitor; Inosine; PD-1; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-025-04111-2
Nat Commun. 2025 Aug 19. 16(1): 7717

Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma.

Amin H Nassar, Chul Kim, Tolulope Adeyelu, Elias Bou Farhat, Hassan Abushukair, Mehrdad Rakaee, Kelsey Matteson, Shun-Fat Lau, Yamato Takabe, Antonio Ocejo, Fatemeh Ardeshir-Larijani, Ticiana Leal, Suresh Ramalingam, Sumaiya Alam, Jhanelle E Gray, James Hicks, David Kaldas, Javier Baena, Maria Zurera Berjaga, Frank Aboubakar Nana, Christian Grohe, Heike Leuders, Fabrizio Citarella, Alessio Cortellini, Emanuele Claudio Mingo, Danny Pancirer, Millie Das, Timothy John Ellis-Caleo, Justin M Cheung, Jessica J Lin, Alexander S Watson, D Ross Camidge, Arthi Sridhar, Kaushal Parikh, Fionnuala Crowley, Thomas U Marron, Vanya Aggarwal, Murtaza Ahmed, Kamya Sankar, Hassan Kawtharany, Jun Zhang, Dwight H Owen, Mingjia Li, Misako Nagasaka, David J Pinato, Nichola Awosika, Khaled Alhamad, Sonam Puri, Unaiza Zaman, Divya M Gupta, Chelsea Lau, Hina Khan, Justin Liauw, Ana I Velazquez, Tyiesha Brown, Laura Moliner, Miguel Mosteiro, Pedro Rocha, Mark Evans, Ari Vanderwalde, Andrew Elliott, Jorge Nieva, Gilberto Lopes, Patrick C Ma, Hossein Borghaei, Matthew Lee, Lauren Young, Raid Aljumaily, Haris Mirza, David J Kwiatkowski, Roy S Herbst, Richard A Flavell, Abdul Rafeh Naqash, Anne C Chiang.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observe comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identifies distinct non-small cell lung cancer-like (NSCLC-like, KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling reveals stable mutational but shifting transcriptomic landscapes over time. Here we show, elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression in NSCLC-like LCNECs, and higher levels of DLL3 in SCLC-like LCNECs. Immunofluorescence confirms FGL-1 expression in NSCLC-like LCNECs, and H&E slide analyses indicates fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC's distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

DOI: https://doi.org/10.1038/s41467-025-63091-0