bims-tuinly 2026-02-15 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–02–15
eighteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

WTX-124, a Conditionally Activated Wild-Type IL2, Maximizes the Therapeutic Index of IL2, Unlike "Non-Alpha" Muteins.
CD274 Alterations and PD-L1 Expression on Tumor Cells and Tumor-Infiltrating Lymphocytes in Patients With Melanoma: Relationships to Histopathologic Features and Outcomes.
Immunophenotyping TCF1-expressing TILs: spatial profiling and prognostic value in operable non-small cell lung cancer.
Ex vivo expansion of melanoma tumor infiltrating lymphocytes leads to a dominant exhausted T cell population with lack of memory markers.
Immunotherapy Approaches for the Treatment of Triple-Negative Breast Cancer.
CD4+ T cells facilitate the RT-induced abscopal effect by promoting antigen cross-presentation to CD8+ T cells at unirradiated tumor sites.
Immune Cell Modulation of Patient-Matched Organoid Drug Response in Precision Cancer Medicine Platform.
Tuning tissue-resident memory T cells to fuel cancer immunotherapy.
Association between tumor-infiltrating lymphocytes and oncotype DX estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 single gene scores in hormone receptor-positive/HER2-negative breast cancer.
Expression Patterns of LALBA and Nucleolin and Their Clinical, Prognostic, and Immune Relevance in Breast Cancer Tissues of Mexican Patients.
Preparation and Evaluation of a Multi-Epitope Peptide for Assessing Immunotherapy of Colorectal Cancer in Vivo.
An Altered Ratio of CD4+ and CD8+ T Lymphocytes in Cervical Cancer Tissue and Peripheral Blood as a Predictor of Prognostic Outcome: A Clinicopathological Study.
Prognostic Significance of Tumour Infiltrating Lymphocytes in Canine Oral Malignant Melanoma Treated With Anti-Programmed Cell Death Ligand 1 (PD-L1) Antibody Therapy.
Cell-derived Nanoparticles Provide a Robust Platform to Manufacture Therapeutic T cells.
Cytometric assessment of antigen-specific T cell signaling.
Securinine bolsters anti-tumor immunity by promoting CD8⁺ T cell activation.
Prognostic impact of weight loss during radiation therapy in patients with head and neck cancer: A systematic review.
Prognostic immunological implications of OX40L expression in the tumor microenvironment of melanoma.

Cancer Immunol Res. 2026 Feb 13. OF1-OF16

WTX-124, a Conditionally Activated Wild-Type IL2, Maximizes the Therapeutic Index of IL2, Unlike "Non-Alpha" Muteins.

Christopher J Nirschl, Kulandayan K Subramanian, Heather R Brodkin, Celesztina Domonkos, Connor J Dwyer, Daniel J Hicklin, Randi Isaacs, Nesreen S Ismail, Julie LePrevost, Yuka Lewis, Kristin Morris, Cynthia Seidel-Dugan, Zoe Steuert, Jenna M Sullivan, Sameer S Chopra, Andres Salmeron, William M Winston.

High-dose interleukin 2 (HD IL2) produces durable responses in patients with advanced cancer, but its use is limited by life-threatening toxicities such as vascular leak syndrome (VLS). To improve the therapeutic index for IL2, a class of IL2 molecules has been engineered to not bind the alpha subunit (CD25) of the high-affinity IL2 receptor. Although these "non-alpha" muteins do not cause VLS, they have other dose-limiting toxicities and have yet to demonstrate antitumor activity comparable with HD IL2. We therefore investigated the potential of a tumor-activated, wild-type IL2 molecule (WTX-124) to improve IL2 tolerability without compromising its efficacy. In mouse models, CD25 engagement by wild-type IL2 was required for optimal activation of tumor-specific CD8+ T cells and for antitumor efficacy. Furthermore, wild-type IL2 was nearly 100-fold more potent than non-alpha IL2 in activating primary human tumor-infiltrating lymphocytes (TIL), even with FoxP3+ regulatory T cells present. Pharmacokinetic-receptor occupancy (PK/RO) modeling showed that by masking wild-type IL2 in the periphery, WTX-124 produces high RO on TILs but low RO on peripheral lymphocytes, unlike non-alpha IL2s. These findings therefore identify the conditional activation of wild-type IL2 as a promising engineering strategy to improve IL2 tolerability without compromising its antitumor activity.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0558
Arch Pathol Lab Med. 2026 Feb 09. pii: earpa.2025-0467-OA. [Epub ahead of print]

CD274 Alterations and PD-L1 Expression on Tumor Cells and Tumor-Infiltrating Lymphocytes in Patients With Melanoma: Relationships to Histopathologic Features and Outcomes.

Aneeza Irfan, Mahyar Khazaeli, Denái R Milton, Priyadharsini Nagarajan, Woo Cheal Cho, Volha Lenskaya, Jonathan L Curry, Carlos A Torres-Cabala, Victor G Prieto, Michael K K Wong, Richard K Yang, Phyu P Aung.

Context.—: In patients with melanoma, the predictive and prognostic relevance of programmed death ligand 1 (PD-L1) protein expression on tumor cells and tumor-infiltrating lymphocytes (TILs) and of alterations in the gene encoding PD-L1, CD274, are not yet established.
Objective.—: To address these gaps in knowledge.
Design.—: We retrospectively evaluated 64 patients with melanoma treated with immune checkpoint blockade therapy (ICBT) who underwent whole genome sequencing. PD-L1 immunohistochemistry using clone 28-8 was available for 33 of 64 patients. Tumor cell PD-L1 expression was categorized as negative (<1% of cells staining), low (1%-10%), or high (>10%), and TIL PD-L1 expression as low (≤30% of TILs expressing PD-L1) or high (>30%). Event-free survival (EFS) and overall survival were assessed in relation to genetic and histopathologic factors.
Results.—: CD274 alterations were identified in 19% (12 of 64) of tumors and were associated with higher tumor mutational burden. Of 33 tumors assessed by immunohistochemistry, 21 showed PD-L1 positivity in tumor cells, which correlated with higher N category, reduced microsatellite stability, and elevated BRAF (B-Raf proto-oncogene, serine/threonine kinase) alteration rate. High PD-L1 expression on TILs was linked to more advanced disease and increased lymphovascular invasion. Among patients with similar clinical stage, patients receiving PD-L1-targeted ICBT had better EFS and overall survival than patients receiving non-ICBT or excision. Notably, patients with gene amplifications of undetermined significance identified on whole genome sequencing had reduced EFS.
Conclusions.—: Our findings suggest that CD274 alterations, PD-L1 expression on tumor cells and TILs, BRAF mutations, genomic amplifications, and tumor mutational burden may provide meaningful prognostic information in patients with melanoma. Prospective validation in larger cohorts is warranted to confirm the utility of these markers in guiding therapeutic decisions.

DOI: https://doi.org/10.5858/arpa.2025-0467-OA
Front Immunol. 2026 ;17 1731337

Immunophenotyping TCF1-expressing TILs: spatial profiling and prognostic value in operable non-small cell lung cancer.

Konstantinos Ntostoglou, Georgios Christodoulopoulos, Katie Stoker, Jean Descarpentrie, Anastasia Xagara, Dora Chatzidaki, Vasiliki Anastasopoulou, Ilias P Nikas, Argyro Ioanna Ieronimaki, Lucy Booth, Sophia Tsoka, Ioannis Vamvakaris, Apostolos Klinakis, Eleni Patsea, Sophia N Karagiannis, Ioannis G Panayiotides, Teresa Frisan, Vassilis Georgoulias, Athanasios Kotsakis, Ioannis S Pateras.

   Background: The spatial distribution and functional heterogeneity of tumor-infiltrating lymphocytes (TILs) significantly impact patient outcomes in non-small cell lung cancer (NSCLC). While T cell factor 1 (TCF1) expressing TILs have emerged as key players in sustaining anti-tumor immunity, their subset characterization, localization, and clinical significance within the tumor microenvironment remain poorly defined.
Method: We performed multiplex immunohistochemistry and immunofluorescence to characterize TCF1+ immune cell subsets, in 102 NSCLC tumors, separately analyzing the tumor center (TC) and invasive front (IF). We integrated this data with publicly available single-cell RNA-sequencing datasets and clinical outcome analyses.
Results: CD4+ T cells and CD79α+ B cells, dominate the TCF1+ landscape, while CD8+ T cells constitute a minority of TCF1+ immune cells, particularly in the TC. We demonstrated the presence of tumor-infiltrating IgG+/IgA+ plasma cells co-expressing TCF1. PD1+TCF1- cells were more frequent than PD1+TCF1+ cells both in the TC and IF, reflecting that terminally differentiated exhausted TILs predominate within the tumor microenvironment. Survival analyses revealed significantly different prognostic impact of TILs including TCF1-expressing cells based on topography. Multivariate analysis showed that increased CD8+TCF1+ cells (HR: 2.5; p=0.039) and increased TCF1 expression by cancer cells (HR: 2,7; p=0.041) in the TC and CD4+TCF1+ cells (HR: 0.4; p=0.043) in the IF emerged as negative and positive independent prognostic markers for Disease-free survival (DFS), respectively. Integrating PD-L1 expression with TILs, PD-L1 immunopositivity was correlated with increased CD8+ and PD1+TCF1- cell infiltration and was associated with favorable DFS especially in the TC.
Conclusions: Our findings support a more refined framework for TCF1+ TIL assessment and TCF1 expression across cellular populations in the tumor microenvironment, with implications for prognostication in operable NSCLC.

Keywords:  T cell factor 1; biomarkers; non-small cell lung cancer; spatial analysis; tumor infiltrating lymphocytes; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1731337
Cancer Immunol Res. 2026 Feb 13.

Ex vivo expansion of melanoma tumor infiltrating lymphocytes leads to a dominant exhausted T cell population with lack of memory markers.

Gianfilippo Coppola, Samuel Kerr, Pei-Chun Cha, Alexey Bersenev, Kelly Olino, Harriet M Kluger, Mario Sznol, Sarah A Weiss, Marcus W Bosenberg, Steven H Kleinstein, Diane S Krause, Michael E Hurwitz, Samuel G Katz.

Tumor infiltrating lymphocytes (TILs) can be isolated from patient tumors, greatly expanded ex vivo, and returned to the patient for therapeutic effect. Recent clinical trials have highlighted the efficacy of TILs for a subset of patients and supported FDA approval for melanoma. How TILs evolve during the manufacturing process is still unknown and likely critical to improving the therapy for more patients. To characterize cell modification during TIL expansion, we performed single-cell RNA- and TCR-sequencing of TILs isolated from patient tumors and their paired ex vivo expanded cell products. We found large transcriptional differences between pre- and post-expansion TILs. Post-expansion TILs were predominantly exhausted and lacked naïve or memory cell phenotypes, including a decreased percentage of CD39/CD69 double negative (DN) "stem-like" T cells. Co-activating receptors CD137 and CD27 decreased while CD30 increased, whereas among co-inhibitory receptors PD1 decreased while TIM3 and LAG3 showed the largest increases with expansion. Other gene families that showed large increases with ex vivo growth included cytotoxicity- and APC-associated genes. Individual clonotypes were distributed among multiple cell differentiation states, which exhibited high degrees of plasticity during expansion. Although ex vivo expanded TILs are predominantly terminally differentiated, exhausted and transcriptionally highly distinct from the initial TILs, there is also a large progenitor exhausted CD8 T cell (Tpex) population and DN numbers increase. Future work to amplify subpopulations of TILs with memory cell phenotypes, such as the DN cells, will likely further improve this therapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0798
Cancers (Basel). 2026 Jan 30. pii: 464. [Epub ahead of print]18(3):

Immunotherapy Approaches for the Treatment of Triple-Negative Breast Cancer.

Shaimaa Alharbi, Farah Faozi Qasem, Mahsa Taleb Talebi, Nourhan E Omran, Rifat Hamoudi, Rania Harati.

  Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high immunogenicity and specific immune signatures. Although these molecular features including elevated tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) expression provide a strong rationale for immunotherapy, clinical response remains limited due to multiple mechanisms of immune escape. This review summarizes current and emerging immunotherapeutic strategies in TNBC, including immune checkpoint inhibitors (PDL-1 and cytotoxic T-lymphocyte-associated protein 4 (CTL-4) blockade), adoptive cell therapy (ACT) (chimeric antigen receptor T-cell therapy (CAR-T) and TIL therapy), oncolytic virotherapy, and antibody-based approaches. We also discuss the mechanisms of resistance including DNA damage response alterations, anti-apoptotic signaling, and tumor microenvironment-mediated resistance. Finally, we highlight rational combination strategies, immunotherapy with chemotherapy, targeted therapy, or additional immunotherapies that aim to enhance response to immunotherapy. Ongoing advances in immunotherapy hold significant potential to improve outcomes for patients with TNBC.

Keywords:  CAR-T cells; PD-1/PD-L1; adoptive cell therapy; antibody–drug conjugates; immune checkpoint inhibitors (ICIs); immune resistance; immunotherapy; oncolytic virotherapy; triple-negative breast cancer (TNBC); tumor microenvironment; tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3390/cancers18030464
J Immunother Cancer. 2026 Feb 10. pii: e013055. [Epub ahead of print]14(2):

CD4+ T cells facilitate the RT-induced abscopal effect by promoting antigen cross-presentation to CD8+ T cells at unirradiated tumor sites.

Xi Rao, Kateryna Onyshchenko, Meidan Wang, Ren Luo, Xuanwei Zhang, Liqun Wang, Siegmar Kuhn, Yizhou Yang, Simone Gaedicke, Anca-Ligia Grosu, Elke Firat, Gabriele Niedermann.

   BACKGROUND: The local effect of radiotherapy (RT) is enhanced by CD8+ T-cell responses elicited through dendritic cell (DC)-mediated cross-presentation of tumor antigens, facilitated by RT-induced damage-associated molecular patterns. The abscopal effect-regression of non-irradiated tumors-has been observed clinically, particularly in combination with immune checkpoint blockade, although it remains uncommon. To better understand how to enhance this effect, we investigated two RT/α-programmed death 1 (PD-1)-based triple combinations incorporating either α-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or CD122-targeted interleukin (IL)-2 complexes (IL-2c).
METHODS: We tested these regimens in B16 melanoma and C51 colon carcinoma models in mice with one irradiated and one non-irradiated tumor on opposite flanks.
RESULTS: In both models, RT/αPD-1/αCTLA-4 elicited a stronger abscopal response than RT/αPD-1/IL-2c. In the C51 model, RT/αPD-1/αCTLA-4 achieved a 61.5% abscopal cure rate, dependent on both CD8+ and CD4+ T cells. In contrast, the less effective RT/αPD-1/IL-2c response required only CD8+ T cells. The enhanced abscopal effect with RT/αPD-1/αCTLA-4 was associated with increased numbers, effector function, and reduced exhaustion of tumor-specific CD8+ tumor-infiltrating lymphocytes (TILs) and of CD4+ TILs, along with elevated CD80+CD86+ DCs in abscopal tumors, as shown by flow cytometry; immunofluorescence confirmed increased T-cell infiltration. CD4+ T-cell depletion during RT/αPD-1/αCTLA-4 treatment impaired abscopal but not irradiated tumor control, reducing infiltration of tumor-specific CD8+ T cells and conventional (c) DC1s, and diminishing cDC1-mediated cross-presentation in abscopal tumors. Activated CD4+ T cells upregulated CD80/CD86 on cDC1s and enhanced cross-presentation, partly via interferon-γ and tumor necrosis factor. Adoptively transferred tumor-specific CD8+ T cells from tumor-irradiated donors localized to unirradiated tumors and draining lymph nodes in αPD-1/αCTLA-4-treated recipients, but not in untreated or CD4+ T cell-depleted mice.
CONCLUSIONS: These results demonstrate that an RT-based combination therapy that robustly induces CD4+ T cells alongside CD8+ T cells can elicit a strong abscopal response and suggest that CD4+ effector T cells act at abscopal sites by promoting DC-mediated cross-presentation of tumor antigens to CD8+ T cells originating from the irradiated tumor.

Keywords:  Abscopal; Immunotherapy; Radiotherapy/radioimmunotherapy

DOI:  https://doi.org/10.1136/jitc-2025-013055
Cells. 2026 Jan 29. pii: 259. [Epub ahead of print]15(3):

Immune Cell Modulation of Patient-Matched Organoid Drug Response in Precision Cancer Medicine Platform.

Silje Kjølle, Mario Presti, Jéssica de Pina Roque, Lina Hua Bisgaard, Darío Beceiro Ramos, Kamilla Westarp Zornhagen, Christina Westmose Yde, Ane Yde Schmidt, Perrine Verdys, Martin Højgaard, Ulrik Lassen, Inge Marie Svane, Kristoffer Staal Rohrberg, Marco Donia, Janine T Erler.

  Cancer is one of the leading causes of death worldwide, and the majority of cancer-related deaths are caused by cancer that has spread to other organs. Precision cancer medicine (PCM) holds potential to improve outcomes and relies on molecularly matched therapies based on cancer cell specific molecular alterations. The tumor immune microenvironment plays an important role beyond response to therapy; however, this is generally not considered in current PCM platforms. We established patient-matched organoids and immune cell cultures for drug testing in mono- and co-culture treatment setups using three distinct treatment strategies (pretreatment, co-culture treatment, and T-cell bispecific antibody testing). Response to treatment and impact of immune cells were evaluated by tumor cell viability assays and flow cytometry analysis. Phenotypic analysis showed high heterogeneity of tumor-infiltrating lymphocytes (TILs) across the patients and low immune cell portions of organoids, emphasizing the need for a patient-matched co-culture PCM approach. Our in-depth study of three patients revealed an effect of the patients' immune cells on drug response and T-cell bispecific antibody treatment in vitro. Here, we illustrate a state-of-the-art co-culture PCM pipeline for patient-matched organoids and immune cells replicating patient response to treatment at the time of biopsy.

Keywords:  3D co-culture platform; immunotherapy; metastasis; precision medicine

DOI:  https://doi.org/10.3390/cells15030259
Int Immunopharmacol. 2026 Feb 11. pii: S1567-5769(26)00151-7. [Epub ahead of print]174 116308

Tuning tissue-resident memory T cells to fuel cancer immunotherapy.

Yao Zhang, Yi-Xuan Fang, Yao Xiao, Shu-Jin Li, Zhi-Jun Sun.

  As the threat of cancer to humanity continues to intensify, immunotherapy has emerged as a promising novel approach in cancer treatment. However, the efficacy of existing immunotherapy varies and needs to be improved urgently. Tissue-resident memory T (TRM) cells, a subset of T cells, have typical tissue-residency characteristics and formidable antitumor potential, which may be a latent enhancer for cancer immunotherapy. Besides, TRM cells are more readily modulated in the process of immunotherapy, compared to other T cell subsets present in the tumor microenvironment. This review summarizes the molecular phenotypes of TRM cells, introduces the relationship between TRM cells and cancer immunology, and proposes a range of potential immunotherapeutic strategies targeting TRM cells. Particularly, this review critically evaluates current clinical strategies and research aimed at modulating TRM cells. These insights are intended to provide new directions for tuning TRM for advancing cancer immunotherapy.

Keywords:  Cancer immunotherapy; Clinical trial; Tissue-resident memory T cells; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.intimp.2026.116308
Front Oncol. 2026 ;16 1677929

Association between tumor-infiltrating lymphocytes and oncotype DX estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 single gene scores in hormone receptor-positive/HER2-negative breast cancer.

Masahiro Ohara, Emi Mikami, Wakako Inohana, Taeko Kurosawa, Ayako Nakame, Ayaka Sakakibara, Yuki Ichinose, Akihiro Fujimoto, Asami Nukui, Aya Asano, Hiroko Shimada, Kyoko Asai, Masataka Hirasaki, Hideki Yokogawa, Kazuo Matsuura, Hiroshi Ishiguro, Takahiro Hasebe, Nobuko Fujiuchi, Akihiko Osaki, Toshiaki Saeki.

   Introduction: Tumor-infiltrating lymphocytes (TILs) are established biomarkers in triple-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancers; however, their clinical significance in hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer remains unclear. This study aimed to investigate the association between TILs and Oncotype DX single gene scores for estrogen receptor (ER), progesterone receptor (PgR), and HER2 in HR+/HER2- breast cancer.
Methods: We retrospectively analyzed 260 patients with HR+/HER2- breast cancer who underwent surgery and Oncotype DX testing at Saitama Medical University International Medical Center between January 2022 and October 2024. TILs were evaluated on hematoxylin and eosin-stained slides according to the International TILs Working Group 2014 guidelines, with high TILs defined as ≥10%. Associations between TILs, clinicopathological factors, and Oncotype DX single gene scores were examined using statistical analyses, including logistic regression. Additionally, publicly available data from The Cancer Genome Atlas (TCGA) cohort were analyzed for validation.
Results: High TIL levels were observed in 32 cases (12.3%). Tumors with high TILs showed significantly lower Oncotype DX single gene expression of ER (9.8 ± 1.9 vs. 10.5 ± 1.3, p < 0.01), PgR (6.3 ± 2.2 vs. 7.4 ± 1.8, p < 0.01), and HER2 (8.5 ± 0.7 vs. 9.2 ± 0.6, p < 0.001) compared with tumors with low TILs. Multivariate analysis identified node-negative status (odds ratio [OR]: 0.266; p = 0.0159) and lower HER2 single gene expression (OR: 0.293; p = 0.00144) as independent predictors of high TILs. TCGA analysis confirmed that lower HER2 mRNA expression was associated with increased chemokine gene expression.
Discussion: In HR+/HER2- breast cancer, tumors with lower HER2 mRNA expression exhibit higher lymphocytic infiltration, suggesting the presence of a distinct immunologically active subset. Oncotype DX single gene scores, particularly HER2, may provide information beyond recurrence risk prediction and help identify patients who may benefit from immune-modulating therapeutic strategies.

Keywords:  RT-PCR; breast cancer; hormone receptor-positive/humanepidermal growth factor receptor 2-negative breast cancer; oncotype Dx; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fonc.2026.1677929
Int J Mol Sci. 2026 Feb 05. pii: 1561. [Epub ahead of print]27(3):

Expression Patterns of LALBA and Nucleolin and Their Clinical, Prognostic, and Immune Relevance in Breast Cancer Tissues of Mexican Patients.

Mariana Navarro-Real, Juan Omar Zavala-López, Juliana Marisol Godínez-Rubí, Antonio Quintero-Ramos, Alicia Del Toro-Arreola, Ramon Franco-Topete, Ángel Quiroz Bolaños, Antonio Topete, Adrián Daneri-Navarro.

  Breast cancer is the most common and deadliest cancer among women. While overexpression of specific markers guides disease stratification and has enabled the development of targeted therapies, identifying new therapeutic targets remains critical, particularly for aggressive subtypes lacking effective treatments. This study evaluated the expression of α-Lactalbumin (LALBA) and nucleolin (NCL) in breast cancer tissues from Mexican patients using gene expression analysis and immunohistochemistry. LALBA, a major milk protein normally expressed only during late pregnancy and lactation, was detected in nearly all tumor samples and showed higher levels in aggressive subtypes, with overexpression displaying a slight trend toward poorer overall survival. NCL, a multifunctional nucleolar protein, exhibited predominantly nuclear localization, with moderate expression associated with improved survival. Both proteins correlated with tumor immune features, including increased tumor-infiltrating lymphocytes (TILs) and PD-L1 expression for LALBA, and elevated CD8+ T cells, PD-L1, and TIM-3 expression for NCL. Overall, these findings suggest that LALBA and NCL are associated with tumor aggressiveness, immune context, and survival trends in breast cancer. Additional studies in larger cohorts are needed to define their clinical relevance.

Keywords:  LALBA; PD-L1; TILs; Tim-3; breast cancer; nucleolin

DOI:  https://doi.org/10.3390/ijms27031561
Protein J. 2026 Feb 09.

Preparation and Evaluation of a Multi-Epitope Peptide for Assessing Immunotherapy of Colorectal Cancer in Vivo.

Fatemeh Bahramibanan, Meysam Soleimani, Amir Taherkhani, Hamidreza Ghadimipour, Rezvan Najafi, Nastaran Barati, Katayoun Derakhshandeh.

  The presence of tumor heterogeneity is a critical issue that restricts the success of targeted therapies and negatively impacts patient outcomes. Recent studies have concentrated on the development of multi-epitope peptides that exhibit considerable overexpression in cancerous tissues with the aim of activating immune cells and utilizing immune-mediated responses to effectively suppress tumor growth. In this study, genes with increased expression in colorectal cancer (CRC) were identified using GEO data and R software. Following overexpression confirmation of APCDD1, we identified epitopes from the protein that can be recognized by various MHC molecules and presented on APC cell surfaces. Subsequent to expression and purification of the multi-epitope peptide and investigation on the BALB/c mice harboring tumor xenograft, obtained results showed a significant reduction in tumor growth, mitotic cell count, angiogenesis, metastasis, and an increase in Tumor-Infiltrating Lymphocytes (TILs) in the tumor microenvironment. Overall, the finding highlight the potential of multi-epitope peptide in CRC immunotherapy, where it may address the significant challenge of tumor heterogeneity.

Keywords:  Colorectal cancer; Immunotherapy; MHC I receptor; MHC II receptor; Multi-epitope peptide; Recombinant peptide

DOI:  https://doi.org/10.1007/s10930-026-10322-y
Asian Pac J Cancer Prev. 2026 Feb 01. pii: 92069. [Epub ahead of print]27(2): 643-649

An Altered Ratio of CD4+ and CD8+ T Lymphocytes in Cervical Cancer Tissue and Peripheral Blood as a Predictor of Prognostic Outcome: A Clinicopathological Study.

Dipimay Das, Harris Mahammad Sepai, Suparna Kanti Pal, Bidhan Chandra Chakraborty, Arpan Adhikary, Miranda Thoudam.

   OBJECTIVE: The aim of our study is to compare CD4+ & CD8+ T lymphocytes in the cervical tumor tissue with those in peripheral blood in patients with carcinoma cervix and to access thier association with known prognostic factors. The study also aims to investigate the association between tumor infiltrating lymphocytes (TILs) and the HPV status of the patients.
METHODS: In this prospective study, 42 patients with locally advanced squamous cell carcinoma of cervix were included. Percentages of CD4+ and CD8+ T lymphocytes were obtained using flow cytometry-based method from single-cell suspension prepared from simultaneously collected tumor tissue and peripheral blood samples. DNA extracted from tumor tissue was analysed to detect HPV16 (Human Papillomavirus 16) and HPV18 infection. T lymphocyte subsets in blood and tumor tissue were compared. The association of T lymphocytes with known prognostic factors and HPV status of the tumor was examined.
RESULT: Both CD4+ and CD8+ T cells were significantly higher in peripheral blood compared to tumor tissue (p < 0.001). The CD4/CD8 ratio was reversed in tumor tissue compared to peripheral blood due to relatively lower reduction of CD8+ cells compared to CD4+ cells in tumor tissue. No significant association of T lymphocyte subpopulation was found with known prognostic parameters of cervical cancer. CD4+ and CD8+ T lymphocyte infiltration was significantly higher in tumor with HPV16 infection (p < 0.05). A significant alteration of CD4/CD8 ratio was observed for HPV18 positive tumors (p < 0.05).
CONCLUSION: Our study demonstrates that both CD4+ and CD8+ T lymphocyte, which are major component of TILs, are significantly lower in tumor tissue compared to peripheral blood in locally advanced cervical cancer. No association was observed between T lymphocyte subpopulations and major prognostic factors of cervical cancer. The enhanced TILs observed in HPV-associated cervical cancer represents a significant alteration with promising therapeutic applications.

Keywords:  CD4/CD8 ratio; HPV; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.31557/APJCP.2026.27.2.643
Vet Comp Oncol. 2026 Feb 12.

Prognostic Significance of Tumour Infiltrating Lymphocytes in Canine Oral Malignant Melanoma Treated With Anti-Programmed Cell Death Ligand 1 (PD-L1) Antibody Therapy.

Shintaro Kamo, Naoya Maekawa, Ayano Kudo, Akinori Yamauchi, Sho Yoshimoto, Yuma Harada, Satoru Konnai, Tomohiro Okagawa, Hayato Nakamura, Yumiko Kagawa, Junichi Kamiie, Keiichi Yamamoto, Satoshi Takagi.

  Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic strategy for canine oral malignant melanoma (OMM). However, only a subset of cases have shown clinical responses. Additionally, predictive biomarkers for the efficacy of ICIs in veterinary medicine are yet to be established. Tumour-infiltrating lymphocytes (TILs) are predictive biomarkers for ICI therapy in humans. In this study, we aimed to investigate the predictive utility of TILs for canine OMM treated with ICI therapy. Immunohistochemistry was performed on pre-treatment pathological tissues to detect cells positive for CD3 (pan-T cell marker), Granzyme B (cytotoxic T lymphocyte or natural killer cell marker) and Foxp3 (regulatory T cell marker). Further, we analysed the infiltration patterns of these cells and their prognostic utility for anti-programmed cell death ligand 1 (PD-L1) antibody therapy. There were variances in the infiltration levels of each TIL subset; further, we observed several TIL infiltration patterns in canine OMM. Survival analysis revealed that high infiltration of CD3+ and Granzyme B+ cells was significantly associated with prolonged progression-free survival and overall survival. Furthermore, the immune cell composition ratio, which reflected the balance between cytotoxic and regulatory cells, was significantly associated with survival time. These findings suggest that canine OMM exhibits immunological phenotypes analogous to those observed in human cancers. Taken together, the TIL profile holds significant potential as a prognostic biomarker for canine OMM treated with anti-PD-L1 antibody therapy.

Keywords:  immune checkpoint inhibitor; oral malignant melanoma; predictive biomarker; tumour infiltrating lymphocytes

DOI:  https://doi.org/10.1111/vco.70052
Res Sq. 2026 Feb 04. pii: rs.3.rs-8436008. [Epub ahead of print]

Cell-derived Nanoparticles Provide a Robust Platform to Manufacture Therapeutic T cells.

James Riley, Mosha Deng, Tanishk Sinha, Meizan Lai, Shuguang Jiang, Hong Kong, Vincent Cooper, Meidi Gu, Jonah Perelman, Caimei Zhang, Chiquita Hanindya, Victor Carpio, Peter Keller, Julie Jadlowsky, Rachel Leskowitz, Stephen McKenna, Megan Four, Jesus Barranco, Natalie Cooper, Ankita Jain, Mercy Gohil, Kathleen Haines, Laura Gerique, Athena Russell, Irina Kulikovskaya, Vanessa Gonzalez, Joseph Fraietta, Gabriela Plesa, Neil Sheppard, Megan Davis, Anne Chew, Noelle Frey, Carl June, Jakub Svoboda, Elizabeth Hexner.

Some patients cannot receive T cell therapies because their cells are unable to be manufactured. To address this limitation, we developed K562-based artificial antigen-presenting cells (aAPCs) expressing an OKT3-derived scFv for TCR stimulation, CD86 and 4-1BBL for costimulation, and membrane-bound IL-7 and IL-15Rα/IL-15 for cytokine support. From these aAPCs, we generated cell-derived nanoparticles (CDNPs) that accelerated T cell entry into the cell cycle compared with CD3/28-coated beads, enabling efficient concurrent activation and lentiviral transduction. CDNPs robustly expanded T cells from patients whose products could not be manufactured using standard approaches, and these CDNP-derived CAR T cells controlled tumors in humanized mouse models. In a phase I trial of patients with CD19⁺ malignancies (NCT04684563), cGMP-compatible CDNPs enabled streamlined 3-day manufacturing of IL-18-expressing CD19 CAR T cells, yielding higher cell recovery and durable clinical responses without unexpected toxicities, supporting CDNPs as a platform for commercial CAR T cell production.

DOI: https://doi.org/10.21203/rs.3.rs-8436008/v1
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00228-6. [Epub ahead of print]202 101-115

Cytometric assessment of antigen-specific T cell signaling.

Zachary H Walsh, Shivem Shah, Johannes C Melms, Benjamin Izar.

  T cell receptor (TCR) signaling strength influences critical T cell characteristics including cytotoxic capacity, differentiation, memory formation, and exhaustion. Naturally occurring or engineered single-nucleotide variants (SNVs) and gene deletions which modulate T cell signaling pathways can significantly impact the potency of T cell cytolytic activity, including in the setting of T cell-based immunotherapies such as tumor-infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor T cell (CAR T) therapy. Thus, studying T cell signaling represents a valuable component of the engineering and preclinical testing process for cell therapies and immune checkpoint blockade (ICB). Flow cytometry is a powerful experimental and diagnostic tool which enables rapid, quantitative analysis of T cell signaling responses by phosphoprotein detection with fluorophore-labeled antibodies. However, many approaches that have been developed to induce and study T cell signaling rely on supraphysiological and non-specific stimulation methods, such as crosslinking of T cell CD3 and CD28 or treatment with chemical stimulating agents such as ionomycin and phorbol 12-myristate 13-acetate (PMA). These assays bypass the endogenous TCR machinery and limit the conclusions which can be drawn regarding the physiological relevance of the T cell responses measured. Here, we present a simple, efficient, and scalable workflow to assess physiological T cell signaling responses to antigen-specific stimulation with cognate peptide-MHC expressing target cells using flow cytometry. With minimal modifications, this approach can be successfully applied to the study of chimeric antigen receptor (CAR) signaling or signaling in other immune cell subtypes such as B cells, using analogous antigen-matched co-culture systems.

Keywords:  Flow cytometry; T cells; TCR signaling; immunology; immunotherapy; phosflow; signaling

DOI:  https://doi.org/10.1016/bs.mcb.2025.11.003
Cancer Treat Res Commun. 2026 Jan 30. pii: S2468-2942(26)00031-6. [Epub ahead of print]47 101120

Securinine bolsters anti-tumor immunity by promoting CD8⁺ T cell activation.

Liangchen Gui, Wenting Song, Haowei Luo, Shuang Zhou, Ye Zhou, Liyuan Zhang, Yunhui Li, Qinlan Wang, Jin Hou.

  Securinine (SEC) is a natural alkaloid isolated from Flueggea suffruticosa, which can suppress tumor growth of some types. T cells play a critical role in anti-tumor function. However, whether SEC mediates T cell-mediated anti-tumor effects remains unknown. Here, we found that SEC treatment suppressed tumor growth and improved survival in tumor-bearing mice in vivo. SEC promotes the percentage of IFN-γ+CD8+ T cell and TNF-α+CD8+ T cell in tumor microenvironments. SEC promoted T cell-mediated cytotoxicity in B16F10-OVA and OT-I co-culture systems. The anti-tumor function of SEC was abrogated after depleting CD8+ T cells in tumor-bearing mice. Mechanistically, SEC promoted T cell receptor (TCR) activation, increased IL-2 and IFN-γ production, and enhanced mitochondrial metabolism in CD8+ T cells. Additionally, SEC combination with anti-PD-1 suppressed tumor growth and improved survival in tumor-bearing mice. Thus, SEC enhances anti-tumor immunity by promoting CD8+ T cell activation, suggesting its potential role in tumor immunotherapy.

Keywords:  Anti-tumor immunity; CD8(+) T cells; PD-1; Securinine

DOI:  https://doi.org/10.1016/j.ctarc.2026.101120
Nutr Health. 2026 Feb 13. 2601060261419743

Prognostic impact of weight loss during radiation therapy in patients with head and neck cancer: A systematic review.

Emelie von Wascinski, Julijana Vracaric, Klaus-Henning Kahl, Stefan Schiele, Anna Rubeck, Lukas Käsmann, Johannes Doescher, Johannes Zenk, Georg Stüben, Maria Neu.

  BackgroundMalnutrition and weight loss (WL) are frequent in patients with head and neck cancer (HNC) during radiotherapy (RT), affecting treatment tolerance and outcomes. Nutritional interventions aim to minimize WL and support therapy completion, yet the prognostic value of WL during RT remains unclear.Aims/ObjectivesTo systematically evaluate the prognostic impact of WL before, during and after RT in patients with HNC.Methods/MethodologyThis systematic review included studies from 2012 involving adult patients treated with definitive or postoperative RT for HNC, studies were eligible if WL/body mass index (BMI) change was analysed versus survival outcomes (overall survival (OS), disease-specific survival (DSS)/cancer-specific survival, disease-free survival (DFS)). A structured PubMed and Cochrane search was conducted and results were synthesized narratively.Results/FindingsEight studies met the inclusion criteria. Pretreatment WL > 10% consistently predicted inferior OS and disease-specific survival (DSS). WL during RT varied widely between studies: most reported no association with OS, whereas single studies reported worse DSS with critical WL, worse OS with ΔBMI >1 kg/m2, or an apparent survival advantage with greater WL. Posttreatment WL ≥ 10% was associated with reduced DFS. Comparability was limited by heterogeneous WL definitions, timing and treatment techniques.ConclusionPretreatment WL is a strong negative prognostic factor in HNC, whereas evidence for WL during or after RT remains inconsistent. Standardized WL assessment and structured nutritional support should be integrated into routine RT care. Future prospective studies using harmonized definitions are needed to clarify prognostic relevance and guide evidence-based nutrition management.

Keywords:  Malnutrition; body mass index; nutritional management; radiation-induced toxicity; supportive care; treatment outcome

DOI:  https://doi.org/10.1177/02601060261419743
Front Immunol. 2026 ;17 1745742

Prognostic immunological implications of OX40L expression in the tumor microenvironment of melanoma.

Susanna Feldman, Baseem Da'ana, Nona Ofek, Liliana Elkis, Adi Pollak-Moseri, Emmanuela Riklin-Nahmias, Sonia Mendlovic, Ayelet Avraham, Raya Leibowitz.

   Background: Immunotherapy targeting immune checkpoint proteins (ICPs) has transformed cancer care, yet current treatments focus on a narrow set of inhibitory ICPs and benefit only a subset of patients. The co-stimulatory pair OX40-OX40L, implicated in inflammation and autoimmunity, also plays roles in cancer immunity. We previously showed that high OX40L mRNA expression in melanoma correlates with favorable prognosis and improved responses to PD-1 blockade. However, the protein-level expression and functions of OX40L in melanoma remain poorly defined.
Methods: Formalin-fixed paraffin-embedded primary tumor samples from 30 patients with stage II-III melanoma were analyzed by multiplex immunofluorescence combined with quantitative image analysis. OX40L and OX40 expression were evaluated alongside immune cell phenotyping markers. Regulatory T cells (Tregs) isolated from human peripheral blood were examined by flow cytometry and RT-qPCR. Associations with recurrence were assessed in depth-matched subsets (n=22) using Kaplan-Meier analysis.
Results: OX40L was detected across tumor, immune, and stromal compartments, with marked intertumoral heterogeneity. OX40+ cells were less frequent but were often found in spatial proximity to OX40L+ cells. OX40L was infrequently detected in melanoma cancer cells, and was more prevalent in antigen-presenting cells, CD4+/CD8+ T cells, and regulatory T cells. Strikingly, intratumoral Tregs expressed OX40L more frequently than OX40 or other ICPs, whereas blood-derived Tregs showed the opposite pattern, with OX40 predominating over OX40L. Disease recurrence following resection of the primary tumor was associated with lower proportions of OX40L-expressing myeloid cells, providing preliminary evidence for a potential link between myeloid OX40L expression and recurrence risk.
Conclusions: OX40L protein expression is a heterogeneous but prominent feature of the melanoma microenvironment, with cell type-specific expression patterns that include regulatory T cells. An exploratory association was seen between myeloid OX40L expression and clinical outcome, warranting further investigation.

Keywords:  OX40L (TNFSF4); melanoma; recurrence/prognosis; regulatory T cells (Treg); tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2026.1745742