bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–06–29
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Engineered immune cell therapies for solid tumors: pharmacological advances, clinical outcomes, and future directions.
  2. Evaluation of tumor budding, desmoplastic reaction, and lymphocytic infiltration in predicting survival for pancreatic ductal adenocarcinoma.
  3. Tumor-Infiltrating Lymphocytes Demonstrate Distinct Behavior in the Tumoral and Peritumoral Microenvironment After Neoadjuvant Chemotherapy in Patients with Resected Adenocarcinoma of the Gastric or Gastroesophageal Junction: Results from a Single Center.
  4. Tumor-Infiltrating Lymphocyte Therapy for the Treatment of Metastatic Melanoma.
  5. Tissue-agnostic biomarkers in solid tumors: current approvals and emerging candidates.
  6. Human cDC1 enhance cytotoxic function of CD226+ terminally exhausted tumor-infiltrating lymphocytes.
  7. Areca nut extract increased stromal tumor-infiltrating lymphocytes in 4-nitroquinoline-1-oxide-tumor-induced Sprague-Dawley rats.
  8. STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy.
  9. Cell-Based Therapies for Solid Tumors: Challenges and Advances.
  10. Role of Preoperative Breast MRI in Predicting Tumor-Infiltrating Lymphocytes in Breast Cancer: Is There an Association with Tumor Biological Subtypes?
  11. Semi-Supervised Contrastive VAE for Disentanglement of Digital Pathology Images.
  12. Breaking down physical barriers: strategies to improve lymphocyte infiltration for effective neoantigen-based therapies.
  13. A Consolidated Review of Contemporary Targeted and Immunotherapeutic Options for Melanoma.
  14. Artificial Intelligence-Powered Spatial Analysis of Immune Phenotypes in Resected Pancreatic Cancer.
  15. GPC2-targeted CAR T cells engineered with NFAT-inducible membrane-tethered IL-15/IL-21 exhibit enhanced activity against neuroblastoma.
  16. Generating tumor-specific T cells based on a head and neck cancer organoid for adoptive cell therapy.
  1. Front Pharmacol. 2025 ;16 1614325
    Engineered immune cell therapies for solid tumors: pharmacological advances, clinical outcomes, and future directions.
    Ziyad M Althafar.
      Solid tumors, accounting for around 90% of human cancers, present unique challenges due to antigen heterogeneity, immunosuppressive microenvironments, and limited accessibility for conventional pharmacotherapies. Immunotherapies, particularly engineered immune cell therapies, exploit the immune-tumor interplay, offering novel pharmacological strategies for solid malignancies. Genetic engineering enhances adoptively transferred cells, such as T cell receptor therapy, chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes (TILs), natural killer cells, and CAR-macrophages, by optimizing their targeting and effector functions. Clinically, TIL delivery has shown significant responses in advanced melanoma, with lifileucel gaining United States FDA approval as a pioneering TIL therapy for solid tumors. Ongoing trials further explore these approaches, revealing promising outcomes in overcoming immunosuppressive barriers. However, challenges persist, including optimizing combination therapies, streamlining manufacturing for off-the-shelf accessibility, and mitigating pharmacotoxicity. This review synthesizes recent advances in engineered immune cell therapies for solid tumors, emphasizing their pharmacological mechanisms, clinical efficacy, and translational potential. By addressing current hurdles, such as enhancing tumor penetration and minimizing adverse effects, this article outlines future directions to refine these therapies as safe, effective pharmacological tools in oncology.
    Keywords:  CAR-T cell therapy; engineered immune cell therapy; pharmacological mechanisms; solid tumor immunotherapy; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fphar.2025.1614325
  2. World J Gastrointest Oncol. 2025 Jun 15. 17(6): 107021
    Evaluation of tumor budding, desmoplastic reaction, and lymphocytic infiltration in predicting survival for pancreatic ductal adenocarcinoma.
    Anıl Alpsoy, Aysen Yavuz, Kubra Simsek, Busra Altunay, Mustafa Karaca, Betul Unal, Cumhur I Bassorgun, Ali M Tatli, Gulsum O Elpek.
       BACKGROUND: Although previous findings indicated that pathological assessment of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may play a role in determining tumor behavior in many malignancies, the relationship between TB, DR, and TILs in patients with pancreatic ductal adenocarcinoma (PDAC) is still unknown.
    AIM: To evaluate relationships of TB, DR, and TILs with histopathological parameters and determine their prognostic value in patients with PDAC.
    METHODS: The study cohort comprised 100 patients diagnosed with PDAC. Peritumoral budding (PTB) and intratumoral budding (ITB) were assessed according to the International Tumor Budding Consensus Conference guidelines. DR was classified based on stromal maturation. TILs were evaluated semiquantitatively with a 5% cutoff. Additionally, cases were categorized into two groups according to lymphocyte density: No/Low lymphocytes and medium/high lymphocytes.
    RESULTS: A significant correlation was observed between ITB and PTB (r = 0.890). Higher PTB was associated with fewer TILs and immature stroma (P < 0.001). PTB and TILs were significantly related to tumor dimension, lymphovascular invasion, lymph node metastasis (LNM), and stage (P < 0.005). ITB was also associated with the presence of lymph node involvement. The results of the univariate analysis revealed a significant correlation between poor survival rates and the presence of lymphovascular invasion, LNM, PTB, ITB, and TILs according to scoring (P < 0.001). The multivariate analysis revealed LNM, PTB, ITB, and TILs according to scoring as independent prognostic factors.
    CONCLUSION: TB assessment stratified patients with PDAC. PTB-ITB correlation showed diagnostic relevance of ITB in biopsy specimens. The prognostic significance of DR and interplay with TIL subsets warrant further investigation.
    Keywords:  Desmoplastic reaction; Pancreatic ductal adenocarcinoma; Prognostic factors; Tumor budding; Tumor microenvironment; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.4251/wjgo.v17.i6.107021
  3. Cancers (Basel). 2025 Jun 13. pii: 1971. [Epub ahead of print]17(12):
    Tumor-Infiltrating Lymphocytes Demonstrate Distinct Behavior in the Tumoral and Peritumoral Microenvironment After Neoadjuvant Chemotherapy in Patients with Resected Adenocarcinoma of the Gastric or Gastroesophageal Junction: Results from a Single Center.
    Fotios Seretis, Antonia Panagaki, Sofia Ritsatou, Eleni Stoupi, Andreas Theodorou, Spyridon Smparounis, Chrysoula Glava, Maria Theochari, Tania Triantafyllou.
      Background/Objectives: Adenocarcinomas of the esophagogastric and gastric areas are often managed with a multimodal treatment including neoadjuvant chemotherapy and surgery. The impact of neoadjuvant chemotherapy on the host's antitumoral immune response remains largely unknown. Methods: A retrospective review of a single-institution cohort of patients with adenocarcinoma of the stomach or esophagogastric area undergoing curative intent surgery after neoadjuvant chemotherapy FLOT (Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel) was reviewed. After institutional ethics approval, pathologic slides were re-reviewed and tumor-infiltrating lymphocyte scores were calculated. Tumor-infiltrating lymphocytes (TILs) were studied in conjunction with tumor regression scores (TRG) and the degree of regression in the involved lymph nodes as well as in correlation with the lymph node ratio (the ratio of involved lymph nodes over the total number of lymph nodes resected). Results: A total of 106 patients were reviewed. No statistical correlation could be established between the tumor-infiltrating lymphocyte scores and the degree of regression in the primary tumor as well as with the partial response to chemotherapy of pathologically involved lymph nodes. The TIL score also did not correlate with the lymph node ratio in our patient cohort. A strong correlation was noted between TILs and lymph nodes that completely regressed after neoadjuvant chemotherapy. Conclusions: Tumor-infiltrating lymphocytes do not correlate with the response of the primary tumor or the partial response of the involved lymph nodes, but only with the complete response to neoadjuvant chemotherapy of tumor-involved lymph nodes. Our study focuses on the effects of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes compared to the effects on the primary tumor and the involved lymph nodes.
    Keywords:  FLOT; chemotherapy; gastric cancer; immune response; lymph nodes; neoadjuvant; regression; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/cancers17121971
  4. Am J Clin Dermatol. 2025 Jun 23.
    Tumor-Infiltrating Lymphocyte Therapy for the Treatment of Metastatic Melanoma.
    Katy K Tsai, Krishna V Komanduri.
      Tumor-infiltrating lymphocyte (TIL) therapy is a type of personalized immunotherapy that harnesses the antitumor activity of endogenous immune cells. While TIL therapy has been in clinical investigation since the 1980s and shown promising signs of clinical activity in immunogenic solid tumors such as melanoma, more recent improvements in product manufacturing and characterization have demonstrated consistent efficacy and the feasibility of administering TIL therapy on a larger scale. Lifileucel was granted accelerated approval by the US Food and Drug Administration in February 2024 for the treatment of advanced melanoma, marking the first regulatory approval of a TIL product, and also the first approval of cellular therapy for the treatment of any solid tumor. Despite this landmark event, questions remain surrounding optimal TIL timing, sequencing with other treatment modalities, and the optimal TIL repertoire and phenotype. Innovations in cellular engineering are expected to improve the antitumor efficacy and safety profile of TIL therapy, advance our understanding of how best to deliver TIL therapy, and provide hope for paradigm-shifting approaches in the treatment of advanced melanoma as well as for other solid tumors.
    DOI:  https://doi.org/10.1007/s40257-025-00957-5
  5. Cancer Metastasis Rev. 2025 Jun 27. 44(3): 58
    Tissue-agnostic biomarkers in solid tumors: current approvals and emerging candidates.
    Jinah Kim, Hye Sung Kim, Myungwoo Nam, Young Kwang Chae.
      The landscape of cancer treatment has shifted from histology-specific to tissue-agnostic approaches, targeting molecular alterations regardless of tumor origin. Currently, six pan-cancer biomarkers-NTRK, BRAF V600E, RET, HER2-positive, MSI-high, and TMB-high-along with nine molecularly targeted therapies have expanded treatment options across diverse malignancies. This review examines each biomarker's molecular basis, prevalence across tumor types, and corresponding FDA-approved therapies. Additionally, emerging candidates-including FGFR, ALK, MET, ROS1, NRG1, PIK3CA, AKT, KRAS G12C, HER2 mutations, HER2-low/ultralow, B7-H3, and tumor-infiltrating lymphocytes (TILs)-are explored. While these biomarkers represent a paradigm shift in oncology, their integration into clinical practice requires overcoming challenges related to tumor heterogeneity and lineage-specific molecular dependencies. Future research should focus on identifying novel biomarkers, optimizing treatment strategies through multiomic analyses, and leveraging innovative clinical trial designs to advance precision oncology. In particular, further investigation into TILs as a predictive biomarker for immunotherapy is warranted, given their distinct immunophenotypic features and prognostic significance in shaping treatment responses across cancer types.
    Keywords:  Immunotherapy; Pan-tumor biomarker; Precision oncology; Targeted therapy; Tissue-agnostic biomarker; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s10555-025-10274-2
  6. Oncoimmunology. 2025 Dec;14(1): 2521391
    Human cDC1 enhance cytotoxic function of CD226+ terminally exhausted tumor-infiltrating lymphocytes.
    Liam O'Brien, Irina Buckle, Ingrid M Leal-Rojas, Nikita Rosendahl, Kristen J Radford.
      Prevention or reversal of T cell exhaustion is a major objective of cancer immunotherapy. However, few models exist to generate, characterize and modulate exhausted human T cells, particularly within solid tumors in vivo, which likely hampers the discovery and translation of novel therapeutics. In this study we describe a humanized mouse model where functional human CD8+ T cells specific for the tumor antigen NY-ESO-1 develop in vivo from human CD34+ hematopoietic stem cells genetically modified to express a HLA-A *0201-restricted NY-ESO-1 specific T cell receptor (TCR). HLA-A *0201+ NY-ESO-1+ expressing A375 melanoma tumors engrafted in these mice and were refractory to treatment with anti-PD-1 despite being infiltrated with NY-ESO-1 specific T cells. Tumor-Infiltrating Lymphocytes (TIL) upregulated tissue resident memory (TRM) markers CD103 and CD69 along with exhaustion markers PD-1, TIGIT, and CD39 relative to T cells from other organs. Further, TILs failed to secrete cytokines TNF and IFNγ following in vitro stimulation with conventional Type I Dendritic Cells (cDC1), indicative of terminal exhaustion. However, cDC1 stimulation of the terminally exhausted NY-ESO-1 specific TILs led to enhanced tumor killing that was associated with increased CD107a and Granzyme B expression that was restricted to a subset of CD226+ NY-ESO-1 specific TILs. These findings establish a novel platform to investigate T cell exhaustion in human tumors and suggest a role for cDC1 in enhancing terminally exhausted TIL cytotoxic function.
    Keywords:  CD226; Humanized mice; T cell exhaustion; cDC1 dendritic cells; melanoma
    DOI:  https://doi.org/10.1080/2162402X.2025.2521391
  7. F1000Res. 2022 ;11 1571
    Areca nut extract increased stromal tumor-infiltrating lymphocytes in 4-nitroquinoline-1-oxide-tumor-induced Sprague-Dawley rats.
    Liza Meutia Sari, Cut Fera Novita, Poppy Andriany, Dina Keumala Sari.
       Background: Oral squamous cell carcinoma (OSCC) is one of the most common oral cancers with a high mortality rate. The biodiversity source in Indonesia makes areca nut a potential antioxidant in treating disease.
    Objective: The study aimed to evaluate the effect of areca nut extract on 4-nitroquinoline-1-oxide (NQO)-tumor-induced rats.
    Methods: Twenty-eight male Sprague-Dawley rats were divided into four groups. Group 1 served as the control group, group 2 was 4NQO-induced rats without treatment, and groups 3 and 4 were given 4NQO-tumor inducer with 500 and 1000 mg/kg BW of areca nut extract, respectively. The rats in groups 2,3, and 4 received 30 ppm of 4NQO tumor inducer in drinking water for 12 weeks. In the end, all rats were euthanized, and the tongue was removed. The body, liver, kidney, heart, and lung weights were measured. Tongue tumor volume and dysplasia lesions were analyzed. The tumor-infiltrating lymphocytes (TILs) in the tumor and stromal areas were scored semi-quantitatively associating the infiltrate grade (0-3) and analyzed histologically.
    Results: There were significant differences in body weight loss between the initial and final phases in groups 1 and 2 (p<0.05). The areca nut at 500 and 1000 mg/kg BW significantly reduced the tumor size compared with groups 1 and 2 (p<0.05). The incidence of OSCC in rats with 500 and 1000 mg/kg BW of areca nut extract after 22 weeks was 0%, but the dysplasia lesions were observed at 28.57% and 85.71%, respectively. The highest mean of stromal TILs was in group 3 and there were significant differences in stromal TILs between groups 2 and 3 (p<0.05).
    Conclusion: Areca nut extract induced infiltrating lymphocytes in the stromal tumor area on the OSCC lesion of the tongue in 4NQO-induced rats.
    Keywords:  4NQO-tumor inducer; Areca nut; Oral cancer; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.12688/f1000research.125784.4
  8. J Immunother Cancer. 2025 Jun 22. pii: e010735. [Epub ahead of print]13(6):
    STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy.
    Fangzhou Sun, Fei Ma, Ting Wang, Yantong Zhou, Dongkui Xu, Hongnan Mo, Chunxiao Li, Jianbin Guo, Zhenguo Zhao, Xiaoqi Yang, Ning Zhong, Ying Zhang, Haili Qian.
       BACKGROUND: T-cell exhaustion is a major barrier to effective antitumor immunity and limits the efficacy of cancer immunotherapies. This study investigates the role of suppressor of T-cell signaling 2 (STS2, also known as UBASH3A) in regulating CD8+ T-cell exhaustion within the tumor microenvironment.
    METHODS: We used genetic ablation of STS2 in mouse models to assess tumor control and responses to anti-programmed cell death protein 1 (PD-1) checkpoint blockade therapy. CD8+ tumor-infiltrating lymphocytes (TILs) were characterized through flow cytometry, mass cytometry, and single-cell transcriptomics. Mechanistic studies included co-immunoprecipitation, protein degradation assays, and endocytosis measurements to elucidate the interplay between STS2 and PD-1.
    RESULTS: STS2 expression progressively increased with T-cell exhaustion. Genetic deletion of STS2 enhanced tumor control and improved responses to anti-PD-1 therapy. STS2-deficient CD8+ TILs maintained a more functional state, exhibiting enhanced effector activity, proliferation, and antitumor efficacy while resisting terminal exhaustion. Mechanistically, we discovered that STS2 physically interacts with PD-1 and modulates its expression, endocytosis, and degradation at the protein level.
    CONCLUSIONS: Our findings establish STS2 as a multifaceted regulator of T-cell exhaustion and highlight its potential as a therapeutic target for enhancing antitumor immunity and improving cancer immunotherapy outcomes.
    Keywords:  Immunosuppression; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2024-010735
  9. Int J Mol Sci. 2025 Jun 09. pii: 5524. [Epub ahead of print]26(12):
    Cell-Based Therapies for Solid Tumors: Challenges and Advances.
    Anna Smolarska, Zuzanna Kokoszka, Marcelina Naliwajko, Julia Strupczewska, Jędrzej Tondera, Maja Wiater, Roksana Orzechowska.
      Solid tumors pose significant therapeutic challenges due to their resistance to conventional treatments and the complexity of the tumor microenvironment. Cell-based immunotherapies offer a promising approach, enabling precise, personalized treatment through immune system modulation. This review explores several emerging cellular therapies for solid tumors, including tumor-infiltrating lymphocytes, T cell receptor-engineered T cells, CAR T cells, CAR natural killer cells, and macrophages. Tumor-infiltrating lymphocytes and their modified versions, T cell receptor-engineered T cells and CAR T cells, provide personalized immune responses, although their effectiveness can be limited by factors like variation in tumor antigens and the suppressive nature of the tumor environment. Natural killer cells engineered with chimeric receptors offer safer, non-major histocompatibility complex-restricted targeting, while modified macrophages exploit their natural ability to enter tumors and reshape the immune landscape. CAR-modified macrophages and macrophages conjugated with drugs are also considered as therapy for solid tumors. The review also examines the implications of autologous versus allogeneic cell sources. Autologous therapies ensure immunologic compatibility but are limited by scalability and manufacturing constraints. Allogeneic approaches offer "off-the-shelf" potential but require gene editing to avoid immune rejection. Integrating synthetic biology, gene editing, and combinatorial strategies will be essential to enhance efficacy and expand the clinical utility of cellular immunotherapies for solid tumors.
    Keywords:  cancer; cell-based therapy; solid tumors
    DOI:  https://doi.org/10.3390/ijms26125524
  10. Biomedicines. 2025 Jun 02. pii: 1364. [Epub ahead of print]13(6):
    Role of Preoperative Breast MRI in Predicting Tumor-Infiltrating Lymphocytes in Breast Cancer: Is There an Association with Tumor Biological Subtypes?
    Silvia Gigli, Emanuele David, Giacomo Bonito, Luisa Favale, Silvia di Sero, Antonio Vinci, Lucia Manganaro, Paolo Ricci.
      Introduction: A potential prognostic biomarker for predicting the response to immunotherapy in breast cancer (BC) is tumor-infiltrating lymphocytes (TILs). The purpose of this research is to examine if preoperative characteristics of breast magnetic resonance imaging (MRI) may be used to predict TIL levels in a group of BC patients. In addition, we aimed to assess any potential relationship between the various tumor biology subgroups and MR imaging characteristics. Materials and Methods: This retrospective analysis comprised 145 participants with histologically confirmed BC who had preoperative DCE MRI. We collected and examined patient information as well as tumor MRI features, such as size and shape, edema, necrosis, multifocality/multicentricity, background parenchymal enhancement (BPE), and apparent diffusion coefficient (ADC) values. We divided patients into two groups based on their TIL levels: low-TIL (<10%) and high-TIL groups (≥10%). Following core needle biopsy, tumors were categorized as Luminal A, Luminal B, HER2+, and Triple Negative using immunohistochemical analysis. TIL levels were correlated with tumor biological profiles and MRI features using both parametric and non-parametric tests. Results: Patients were categorized as having a high TIL level (≥10%; 54/145 patients) and a low TIL level (<10%; 91/145 patients) based on the median TIL level of 10%. Of the lesions, 13 were HER2-positive, 16 were Triple Negative, 49 were Luminal A, and 67 were Luminal B. Higher TIL levels were statistically correlated with TNBC (11/16 individuals, p: 0.007). ADC values (p = 0.01), BPE levels (p = 0.008), and TIL levels were all significantly negatively correlated. Significantly more homogenous enhancement was seen in tumors with elevated TIL levels (p = 0.001). The ADC values and the enhancing characteristics were the most important factors in predicting TIL levels, according to logistic regression analysis, and when combined, they demonstrated the strongest ability to distinguish between the two groups (AUC = 0.744). Conclusions: MRI features, particularly ADC values and enhancement characteristics, may play a pivotal role in the assessment of TIL levels in BC before surgery. This could help patients to better customize treatments to the features of their tumors.
    Keywords:  apparent diffusion coefficient; breast cancer; immunotherapy; magnetic resonance imaging; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/biomedicines13061364
  11. Med Image Comput Comput Assist Interv. 2024 Nov;15004 459-469
    Semi-Supervised Contrastive VAE for Disentanglement of Digital Pathology Images.
    Mahmudul Hasan, Xiaoling Hu, Shahira Abousamra, Prateek Prasanna, Joel Saltz, Chao Chen.
      Despite the strong prediction power of deep learning models, their interpretability remains an important concern. Disentanglement models increase interpretability by decomposing the latent space into interpretable subspaces. In this paper, we propose the first disentanglement method for pathology images. We focus on the task of detecting tumor-infiltrating lymphocytes (TIL). We propose different ideas including cascading disentanglement, novel architecture, and reconstruction branches. We achieve superior performance on complex pathology images, thus improving the interpretability and even generalization power of TIL detection deep learning models. Our codes are available at https://github.com/Shauqi/SS-cVAE.
    Keywords:  Contrastive VAE; Digital Pathology; Disentanglement
    DOI:  https://doi.org/10.1007/978-3-031-72083-3_43
  12. Front Immunol. 2025 ;16 1614228
    Breaking down physical barriers: strategies to improve lymphocyte infiltration for effective neoantigen-based therapies.
    Ting-Ting Chen, Xiong Li, Yi Zhang, Xiao-Juan Kang, Shu-Fang Zhang, Tong Zhang, Deji Sangmao, Ya-Juan Zhu, De-Kui Zhang.
      The cancer genomic instability drives the generation of neoantigens, making them ideal targets for immunotherapy. Neoantigen-specific tumor-infiltrating lymphocytes achieve precise tumor cell killing by recognizing neoantigens on the tumor surface, but their efficacy is limited by complex physical barriers within the tumor microenvironment. These barriers not only directly impede TIL migration and infiltration but also synergize with immunosuppressive signals to weaken antitumor immune responses. The tumor extracellular matrix forms a dense fibrous network due to enhanced collagen crosslinking, pathological hyaluronic acid deposition, and increased stiffness, hindering TIL mobility. Aberrant tumor vasculature, characterized by hyperpermeability and elevated interstitial fluid pressure, collaborates with pro-fibrotic factors, such as VEGF, TGF-β secreted by cancer-associated fibroblasts and regulatory T cells to create mechanical compression barriers. This review systematically explores the composition, molecular mechanisms, and therapeutic strategies targeting these physical barriers, providing novel insights for neoantigen-based therapies. Future efforts should integrate biomechanical interventions with immunotherapy, elucidate the interplay between mechanical signaling and immunometabolism, and optimize multi-target combinatorial approaches to enhance the clinical translation potential of neoantigen therapies.
    Keywords:  cancer-associated fibroblasts; extracellular matrix; interstitial fluid pressure; neoantigen; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2025.1614228
  13. Biomedicines. 2025 Jun 05. pii: 1388. [Epub ahead of print]13(6):
    A Consolidated Review of Contemporary Targeted and Immunotherapeutic Options for Melanoma.
    Parker J Champion, Jacob R Bluestein, Anthony E Quinn, Scott D Bell, Josiah H Kiley, Mark R Wakefield, Yujiang Fang.
      The incidence of melanoma is increasing globally, even in the wake of increased risk factor awareness and a growing body of advanced therapeutic options. It is apparent that the treatment of melanoma will remain a topic of worry in areas of the world under high ultraviolet exposure and areas that harbor individuals with fair skin phenotypes. In the wake of such concern, the potential of immunotherapy and various targeted therapeutics to treat late-stage melanoma is increasing. In addition to the growing arsenal of PD-1 and PD-L1 immune checkpoint inhibitors, other targeted therapies are being developed and tested to treat melanoma. BRAF/MEK inhibitors target a key proliferative pathway in melanoma, offering clinical benefit but limited durability. Next-generation agents and triplet therapy with immunotherapy aim to improve outcomes. Androgen receptor signaling may also modulate responses to both targeted and immune-based treatments. Bispecific T cell engagers assist with guiding the body's own T cells to tumors where they release toxins that kill the tumor cell. Personalized neoantigen vaccines target tumor-specific antigens by sequencing a patient's cancerous cells to create tailored vaccines that elicit a strong and specific immune response. Tumor-infiltrating lymphocytes are autologous lymphocytes reinfused back into the host that are showing efficacy in the treatment of advanced melanoma. Together, these therapies are advancing the arsenal of chemotherapeutic options that can be used to inhibit the progression of melanoma.
    Keywords:  cancer; immunotherapy; melanoma
    DOI:  https://doi.org/10.3390/biomedicines13061388
  14. JAMA Surg. 2025 Jun 25.
    Artificial Intelligence-Powered Spatial Analysis of Immune Phenotypes in Resected Pancreatic Cancer.
    Hyemin Kim, Jin Ho Choi, Yoojoo Lim, So Jeong Yoon, Kee-Taek Jang, Chan-Young Ock, Young Hoon Choi, Cheolyong Joe, Sanghoon Song, Jimin Moon, Heon Song, Sergio Pereira, Seungeun Lee, Sujin Park, Kyunga Kim, Se-Hoon Lee, Hongbeom Kim, Sang Hyun Shin, Jin Seok Heo, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Lee, In Woong Han, Joo Kyung Park.
       Importance: Although tumor-infiltrating lymphocytes (TILs) have been implicated as prognostic biomarkers across various malignancies, the clinical application remains challenging. This study evaluated the applicability of artificial intelligence (AI)-powered spatial mapping of TIL density for prognostic assessment in resected pancreatic ductal adenocarcinoma (PDAC).
    Objective: To evaluate the prognostic significance of AI-powered spatial TIL analysis in resected PDAC and its clinical applicability.
    Design, Setting, and Participants: This cohort study included patients with PDAC who underwent up-front R0 resection at a tertiary referral center between January 2017 and December 2020. Whole-slide images of retrospectively enrolled patients with PDAC and up-front R0 resection were analyzed. An AI-powered whole-slide image analyzer was used for spatial TIL quantification, segmentation of tumor and stroma, and immune phenotype classification as immune-inflamed phenotype, immune-excluded phenotype, or immune-desert phenotype. Study data were analyzed from January 2017 to August 2023.
    Exposure: Use of AI-powered spatial analysis of the tumor microenvironment in resected PDACs.
    Main Outcomes and Measures: Tumor microenvironment-related risk factors and their associations with overall survival (OS) and recurrence-free survival (RFS) outcomes were identified.
    Results: Among 304 patients, the mean (SD) age was 66.8 (9.4) years with 171 male patients (56.3%), and preoperative clinical stages I and II were represented by 54.3% patients (165 of 304) and 45.7% patients (139 of 304), respectively. The TILs in the tumor microenvironment were predominantly concentrated in the stroma, and the median intratumoral TIL and stromal TIL densities were 100.64/mm2 (IQR, 53.25-121.39/mm2) and 734.88/mm2 (IQR, 443.10-911.16/mm2), respectively. Overall, 9.9% of tumors (30 of 304) were immune inflamed, 85.2% (259 of 304) were immune excluded, and 4.9% (15 of 304) were immune desert. The immune-inflamed phenotype was associated with the most prolonged OS (median not reached; P < .001) and RFS (median not reached; P = .001), followed by immune-excluded phenotype and immune-desert phenotype. High intratumoral TIL density was associated with longer OS (median, 52.47 months; 95% CI, 41.98-62.96; P = .004) and RFS (median, 21.67 months; 95% CI, 14.43-28.91; P = .02). A combined analysis of the pathologic stage with immune phenotype predicted better survival of stage II PDAC stratified as immune-inflamed phenotype than stage I PDAC stratified as non-immune-inflamed phenotype.
    Conclusions and Relevance: Results of this cohort study suggest that the use of AI has markedly condensed the labor-intensive process of TIL assessment, potentially rendering the process more feasible and practical in clinical application. Importantly, the IP may be one of the most important prognostic biomarkers in resected PDACs.
    DOI:  https://doi.org/10.1001/jamasurg.2025.1999
  15. Cancer Immunol Res. 2025 Jun 26.
    GPC2-targeted CAR T cells engineered with NFAT-inducible membrane-tethered IL-15/IL-21 exhibit enhanced activity against neuroblastoma.
    Reona Okada, Jeyshka M Reyes-González, Constanza Rodriguez, Taisuke Kondo, Jangsuk Oh, Ming Sun, Michael C Kelly, Ling Zhang, James L Gulley, Jack F Shern, Mitchell Ho, Christian S Hinrichs, Naomi N Taylor, Xiyuan Zhang, Rosa Nguyen.
      Neuroblastoma (NB) is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in NB, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR optimization. One approach to addressing the high tumor burden involves engineering CAR T cells to release or express transgenic cytokines. However, its systemic toxicity remains an important therapeutic challenge. Here, we evaluated the efficacy of interleukin (IL)-15- and IL-21-enhanced glypican-2 (GPC2)-targeted CAR T cells (GPC2-CAR T cells) in targeting high-burden NB. Three strategies for expressing the cytokines were evaluated: constitutive secretion (GPC2-CAR+sol.IL15.IL21), constitutive membrane-tethered expression (GPC2-CAR+teth.IL15.IL21), and NFAT-inducible membrane-tethered expression (GPC2-CAR+NFAT.IL15.IL21). Engineered GPC2-CAR T cells were tested in vitro and in vivo using high NB-burden xenograft models. Additionally, single-cell RNA sequencing was used to profile the effector cells in the tumor microenvironment. All three versions of GPC2-CAR T cells significantly enhanced killing against a high NB burden, both in vitro and in vivo, relative to control GPC2-CAR T cells. Mice treated with GPC2-CAR+NFAT.IL15.IL21 exhibited significantly lower anorexia-associated morbidity/mortality. Supporting these data, tumor-infiltrating GPC2-CAR+NFAT.IL15.IL21 developed an immunosuppressive transcriptional profile upon tumor regression, leading to prolonged survival in treated mice. In contrast, GPC2-CAR+teth.IL15.IL21 maintained a pro-inflammatory transcriptional signature despite near tumor clearance, resulting in hypercytokinemia and death. NFAT-inducible co-expression of tethered IL-15/IL-21 enhanced GPC2-CAR T-cell function against a high NB burden with acceptable tolerability in mice. Further studies are required to validate these findings.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0975
  16. Front Immunol. 2025 ;16 1573965
    Generating tumor-specific T cells based on a head and neck cancer organoid for adoptive cell therapy.
    Yinyu Chen, Shoupeng Wang, Luxi Zheng, Lin Chen, Feng Xu, Shuqi Guo, Jian Meng.
       Background: A head and neck cancer organoid (HNCO) and peripheral blood T cell co-culture model was established to investigate whether HNCOs can induce the differentiation of peripheral blood T cells into tumor-reactive T cells. Additionally, this study seeks to explore the cytotoxicity of these T cells against autologous tumor organoids, providing theoretical and experimental evidence for the feasibility of this model as a platform for adoptive cell immunotherapy in head and neck cancer (HNC).
    Methods: HNCO single cells were co-cultured with peripheral blood lymphocytes (PBLs) collected and isolated from patients with HNC. The culture supernatant was collected and assayed for interferon-gamma (IFN-γ) and tumor necrosis factor-α (TNF- α). The expression of T cell activation markers cluster of differentiation (CD)137 and CD107a was measured by flow cytometry to confirm tumor specificity and cytotoxicity. Additionally, the optimal effector-to-target (E/T) ratio was determined using the Cell Counting Kit-8 assay, and HNCO killing was quantified by fluorescent labeling.
    Results: Of the 27 successfully established HNCO-T cell co-culture systems, 81.48% induced the in vitro differentiation and tumor-reactive CD8+ T cell expansion capable of mediating the killing of mature HNCOs.
    Conclusion: The patient-derived HNCO-T cell co-culture model effectively induced PBL differentiation into tumor-reactive CD8+ T cells with enhanced tumor-killing activities. This model serves as a novel in vitro preclinical tool for advancing personalized adoptive immunotherapy in HNC.
    Keywords:  adoptive cell therapy; co-culture; head and neck cancer; organoid; peripheral blood T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1573965
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