bims-tuinly 2026-01-18 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–01–18
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Tumor-Infiltrating Lymphocytes (TILs), for Patients with Triple-Negative Breast Cancer.
Characteristics and developmental trajectory of clinical trials focused on tumor-infiltrating lymphocytes for cancer treatment.
T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.
Characterization of tumor-associated macrophages in canine soft tissue sarcomas reveals histotype-dependent immune microenvironments and correlations with mitotic count and histological grade.
Cell therapy in sarcoma: current landscape and future directions.
Predicting anti-PD-1 immune checkpoint blockade response in melanoma patients with spatially aware machine learning models.
Latent Regulatory Programs Generate Synthetic T Cell States with Enhanced Therapeutic Potential.
IL7-TBRII, a Dual Cytokine Modulator Targeting IL-7 and TGF-β Pathways, Inhibits Tumor Progression and Metastasis.
Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models.
Prognostic significance of p16 and immune cell infiltration in recurrent/metastatic head and neck squamous cell carcinoma treated with PD-1 inhibition: a national DAHANCA cohort study.
T cell receptor-engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models.
HLA-DR+ CD8+ T lymphocytes as an alternative T-cell activation marker in pediatric HLH: A real-life study.
The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction.
Role of tumor‑infiltrating lymphocytes and miR‑155 in breast cancer: Insights into carcinogenesis and their potential as prognostic biomarkers (Review).
Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.
DNA prime and peptide boost immunization elicits robust neoantigen-specific CD8 + T cell responses and therapeutic protection in mouse tumor models.
Proteotranscriptomic Dissection of Breast Cancer T Cell States Identifies CD103+ Tfh-derived Cytotoxic Cells Linked to Immunotherapy Response.
BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells.
Fully human anti-B7-H4 antibody induces lysosome-dependent ferroptosis to reverse primary resistance to PD-1 blockade.

Cancer Invest. 2026 Jan 12. 1-8

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Tumor-Infiltrating Lymphocytes (TILs), for Patients with Triple-Negative Breast Cancer.

Marcela Soto, María Teresa Poblete, Pamela Erhenfeld, Diego Halabi.

  During the process of carcinogenesis, inflammation originating in the tumor or its microenvironment promotes tumor growth. An elevated neutrophil-lymphocyte ratio (NLR) has been considered a biomarker associated with reduced survival in several types of cancer. A retrospective study was conducted and the results of 49 triple-negative breast cancer (TNBC) biopsies from 2012 to 2017 were reviewed. The patients were divided into two groups: those with nonbasal subtype TNBC and those with basal-like TNBC. To differentiate TNBC tumors by subtype, cytokeratin 5/6 (CK5/6) expression was assessed. The Chi-square test was used to analyze the association between the classical clinicopathological parameters and these two groups, revealing a statistically significant relationship with histological grade. For overall survival, the Kaplan-Meier method was used to analyze the data. The difference in survival was compared by univariate analysis. Patients with elevated tumor-infiltrating lymphocytes (TILs) and a NLR less than 3 had prolonged survival. NLR is a cost-effective and reliable tool that can be exploited in a wide number of scenarios during daily clinical practice.

Keywords:  Breast cancer; Neutrophil-lymphocyte ratio; Overall survival; Triple-negative; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1080/07357907.2025.2612595
Cancer Gene Ther. 2026 Jan 14.

Characteristics and developmental trajectory of clinical trials focused on tumor-infiltrating lymphocytes for cancer treatment.

Jinyi Liu, Chun Xiao, Wei Zhang, Xinhong Li, Xuebin Wang.

Tumor-infiltrating lymphocytes (TIL) have shown promise in cancer immunotherapy, yet their clinical application and developmental trajectory remain insufficiently characterized. In this study, we conducted a cross-sectional, descriptive analysis of interventional clinical trials investigating TIL therapies for cancer treatment registered on ClinicalTrials.gov up to December 31, 2024. Trial characteristics, temporal trends, and treatment strategies were systematically assessed. Among 177 eligible trials, the vast majority were early-phase studies enrolling small patient cohorts. Malignant melanoma was the most frequently studied tumor type. North America conducted the largest number of trials overall, while recent years have seen rapid growth in trial activity and industry sponsorship, particularly in Asia. Cytokine support and immune checkpoint inhibitors (ICIs) were the most common combination strategies. Since 2017, increasing interest has been observed in TIL monotherapy and in TIL-ICI combinations. Genetically engineered TIL trials were less likely to incorporate cytokine support or non-myeloablative chemotherapy, whereas selectively expanded TIL trials more frequently evaluated radiotherapy as a combination strategy. Overall, clinical trials of TIL therapy have primarily focused on early-phase exploration. Cytokines and ICIs remain the predominant combination approaches, while the use of TIL monotherapy has emerged as a growing trend. Continued research efforts and clinical investigation are essential to support the broader and more standardized application of TIL-based therapies in cancer treatment.

DOI: https://doi.org/10.1038/s41417-026-00998-w
Adv Sci (Weinh). 2026 Jan 12. e20634

T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.

Yang Yu, Xiaoyu Yao, Qingyang Wang, Mengrui Yang, Runze Li, Jiangjiang Qin, Jing Zhuang, Changgang Sun.

  T cell exhaustion represents a pivotal mechanism of immune escape in cancer, with its inherent heterogeneity and dynamic plasticity being key determinants of the variable responses and resistance to immune checkpoint inhibitors (ICIs). This review comprehensively delineates the multifaceted heterogeneity of exhausted T (TEX) cells, tracing their developmental trajectory from precursor exhausted T (TPEX) cells to terminally differentiated exhausted T (TEX -term) cells. We highlight both distinct and shared exhaustion features across diverse cancer types and spatial niches within the tumor microenvironment. Furthermore, we examine the multi-layer biomarkers that drive and define this state, including characteristic surface inhibitory receptors, core transcription factors, and metabolism-associated molecules. Grounded in this mechanistic understanding, we discuss emerging therapeutic strategies aimed at reversing T cell exhaustion. These range from the optimized application of ICIs and rational combination therapies involving epigenetic or metabolic interventions, to next-generation engineered cell therapies such as chimeric antigen receptor T cell (CAR-T), T cell receptor-engineered T cell (TCR-T), and tumor-infiltrating lymphocytes (TILs), alongside emerging modalities including oncolytic viruses and bispecific antibodies. Finally, we discuss prevailing challenges and future directions, emphasizing that deciphering the heterogeneous landscape of TEX cells, identifying precise biomarkers, and developing temporally controlled combination regimens are imperative to effectively reverse T cell exhaustion and broaden the therapeutic efficacy of cancer immunotherapy.

Keywords:  T cell exhaustion; cancer immunotherapy; combination therapy; immune checkpoint inhibitors; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202520634
Vet Pathol. 2026 Jan 11. 3009858251409221

Characterization of tumor-associated macrophages in canine soft tissue sarcomas reveals histotype-dependent immune microenvironments and correlations with mitotic count and histological grade.

Giancarlo Avallone, Elena Brigandì, Antonella Rigillo, Barbara Bacci, Chiara Tugnoli, Paola Roccabianca.

  The tumor-immune microenvironment (TIME) plays a pivotal role in cancer progression, yet its characterization in veterinary oncology remains limited. Eighty-five soft tissue sarcomas (STSs), comprising fibrosarcomas, leiomyosarcomas, liposarcomas, myxosarcomas, and perivascular wall tumors (PWTs), were immunohistochemically assessed for IBA-1 (total tumor-associated macrophages) and CD204 (M2-like macrophages) expression, scored by image analysis, and correlated with histological parameters. IBA-1 was higher in grade 3 STSs compared with grade 1 (W = 3.40, P = .043) and in PWTs compared with myxosarcomas (W = 6.037, P < .001). CD204 was lower in PWTs compared with fibrosarcomas (W = 5.152, P = .003), leiomyosarcomas (W = 4.394, P = .016), and myxosarcomas (W = 4.812, P = .006). Stratifying by STS type, IBA-1 was higher in grade 2 myxosarcomas compared with grade 1 (Mann U = 4, P = .018). IBA-1 and CD204 were higher in myxosarcomas with necrosis compared with those without (Mann U = 5, P = .026, and Mann U = 0, P = .001, respectively). In PWTs, the mitotic count was higher in cases with higher IBA-1 (Spearman's rho = 0.438, P = .041) and cases with lower CD204 (Spearman's rho = -0.459, P = .035). Considering all STSs, IBA-1 correlated with total tumor-infiltrating lymphocytes (TILs), T-cells, and regulatory T-cells (Tregs). In fibrosarcomas, IBA-1 and CD204 directly correlated with total TILs, T-cells, and Tregs. In myxosarcomas, CD204 correlated with Tregs. In leiomyosarcomas, IBA-1 scores correlated with Tregs and CD204 with T-cells and Tregs. In PWTs, B-cells correlated with IBA-1 and inversely correlated with CD204. These findings suggest the presence of a TIME favoring anti-tumor immunity in PWTs and a pro-tumoral TIME in myxosarcomas, reinforcing the concept that canine STS histotypes elicit distinct immune responses.

Keywords:  CD204; IBA-1; canine soft tissue sarcomas; digital image analysis; immunohistochemistry; tumor-associated macrophages; tumor-immune microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1177/03009858251409221
J Immunother Cancer. 2026 Jan 12. pii: e013396. [Epub ahead of print]14(1):

Cell therapy in sarcoma: current landscape and future directions.

Taha Koray Sahin, Theodora Germetaki, Deniz Can Guven, Serkan Akin, Omer Dizdar, Fiona Thistlethwaite, Elizabeth A Connolly, Kok Haw Jonathan Lim.

  Sarcomas are rare malignancies of mesenchymal origin, characterized by significant biological and clinical heterogeneity. Many subtypes demonstrate limited sensitivity to standard systemic treatments, including immune checkpoint inhibitors. Cell therapy has emerged as a promising strategy, with the potential of durable clinical responses seen with genetically-engineered T-cell receptor T-cell therapies (TCR-T) such as those targeting the cancer-testis antigen MAGE-A4 in synovial sarcoma, leading to the US Food and Drug Administration approval of afamitresgene autoleucel in 2024. This constituted only the second approval of a cell therapy in a solid tumor following lifileucel in melanoma and demonstrated the potential of cell therapies in sarcomas. This review provides the current landscape and growing potential of cell therapies in sarcomas, including TCR-T, chimeric antigen receptor-T cells, tumor-infiltrating lymphocytes, natural killer (NK) cells, and mesenchymal stromal cells. However, the broader application of these therapies is hindered by the lack of targetable sarcoma-restricted immunogenic epitopes, spatiotemporal intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment that impedes effector-cell trafficking, expansion and persistence. While cell therapies hold promise for integration into precision medicine approaches for sarcomas, their successful implementation will require careful evaluation of clinical feasibility, logistical considerations and cost-effectiveness to optimize patient outcomes.

Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immunotherapy; T cell Receptor - TCR; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2025-013396
NPJ Precis Oncol. 2026 Jan 12.

Predicting anti-PD-1 immune checkpoint blockade response in melanoma patients with spatially aware machine learning models.

Alyssa Pybus, Raphael Kirchgaessner, Jonathan Nguyen, Carlos Moran Segura, Paulo Cilas Morais Lyra, Trevor Rose, Jhanelle Gray, Jeremy Goecks, Joseph Markowitz.

There is an acute need to accurately identify patients with advanced melanoma who are most likely to respond to anti-PD1 immune checkpoint blockade (ICB) therapy. While anti-PD1 therapy can be highly effective in advanced melanoma patients, only 30-40% of patients respond well. In this study, we apply single-cell spatial proteomics together with statistical and machine learning (ML) methods to successfully predict advanced melanoma patient response to anti-PD1 ICB in a cohort of 12 patients with >8 million cells. While no single molecular feature is sufficient to predict ICB response in our cohort, ML models integrating multiple molecular features accurately predict response in 11 of 12 patients. A recurrent cellular neighborhood analysis revealed a tumor-infiltrating lymphocytes niche that was present in the tumors of most responders. This neighborhood, tumor microenvironment immune cell composition, and levels of nitric oxide synthases were all important features used by our ML models to make accurate predictions. Optimal predictive performance by our ML models-a ROC AUC of 0.76-was achieved when using all molecular features, including cellular spatial relationships, but limiting our analysis to only immune-rich tissue regions. This study demonstrates the feasibility of using machine learning models to accurately predict patient response to anti-PD1 ICB therapy using spatial proteomics datasets.

DOI: https://doi.org/10.1038/s41698-025-01250-8
bioRxiv. 2026 Jan 08. pii: 2026.01.07.698190. [Epub ahead of print]

Latent Regulatory Programs Generate Synthetic T Cell States with Enhanced Therapeutic Potential.

Brandon M Pratt, Genevieve N Mullins, Nolan Brown, William D Green, Jennifer Modliszewski, Fucong Xie, Lara van Rooyen, Vasyl Zhabotynsky, Alexander N Jambor, Gabrielle Cannon, Jarred M Green, Andrew Kennedy, Coral Del Mar Alicea Paunto, Huitong Shi, Emily Merritt, Takeshi Egawa, Ashwin Somasundaram, Wei Wang, Jessica E Thaxton, Gianpietro Dotti, H Kay Chung, J Justin Milner.

Transcription factors (TFs) govern cell fate through coordinated gene-regulatory networks, yet the full potential of these networks to generate non-native, therapeutically advantageous cell states in vivo remains largely unexplored. We hypothesized that systematic gain-of-function (GOF) overexpression of TFs in CD8⁺ T cells, central mediators of immune protection, could reveal latent, or "hidden," regulatory programs capable of generating synthetic T cell states with therapeutic utility. To test this, we developed single-cell GOF sequencing (scGOF-seq), a multiplexed platform for unbiased, in vivo mapping of GOF effects on T cell fate in immunocompetent mouse models of infection and cancer. scGOF-seq uncovered unexpected regulators of T cell differentiation and accumulation, including SOX2, OCT4, and GATA2, which are normally silenced during T cell differentiation. Notably, outside its native regulatory context, supraphysiologic cMyc GOF reprogrammed CD8⁺ T cells into a synthetic stem-effector hybrid state, enabling >5,000-fold antigen-dependent expansion and antitumor activity, contrasting sharply with its native function in driving terminal differentiation. scGOF-seq further identified TF modules that cooperate with cMyc GOF to promote robust CD8⁺ T cell responses in solid tumors. Together, these findings establish GOF perturbation as a powerful strategy for revealing latent immune regulatory programs and engineering synthetic immune states with therapeutic potential.
One-Sentence Summary: In vivo single-cell gain-of-function screening reveals latent transcriptional programs that can reprogram T cells into highly functional synthetic states.

DOI: https://doi.org/10.64898/2026.01.07.698190
Immune Netw. 2025 Dec;25(6): e42

IL7-TBRII, a Dual Cytokine Modulator Targeting IL-7 and TGF-β Pathways, Inhibits Tumor Progression and Metastasis.

Youngsik Oh, Sora Kim, Ji-Hae Kim, Kun-Joo Lee, Dain Moon, Chaerim Jeong, Hyun Gyung Kim, Seung-Min Chun, Mi-Sun Byun, Seung-Woo Lee.

  Tumor-infiltrating CD8+ T cells are a key determinant of anti-tumor efficacy in immunotherapy. IL-7 has been explored as a cytokine therapy to expand CD8+ T cells, showing promising anti-tumor effects in preclinical models. However, clinical outcomes remain limited, likely due to the immunosuppressive tumor microenvironment. To enhance the efficacy of IL-7 therapy, we reanalyzed publicly available single-cell RNA-sequencing (scRNA-seq) data of tumors treated with IL-7, identifying elevated TGF-β signaling in CD8+ T cells following treatment. As TGF-β impairs CD8+ T cell function and antagonizes IL-7 signaling, we developed a bifunctional fusion protein, recombinant human IL-7 (rhIL-7)-hyFc-sTBRII (IL7-TBRII), by fusing a TGF-β trap (Fc-TBRII) to rhIL-7-hyFc (IL7-Fc). We evaluated the binding affinities and functionalities of each domain in vitro and in vivo, and assessed anti-tumor effects in the MC38 colon cancer model. IL7-TBRII demonstrated superior anti-tumor efficacy compared to IL7-Fc or Fc-TBRII alone, primarily through increased infiltration of cytotoxic CD8+ T cells into tumors. Also, IL7-TBRII expanded the number of activated CD44+ CD8+ T cells. Furthermore, IL7-TBRII reduced metastasis in the 4T1 breast cancer model by reshaping the immune cell composition, and demonstrated synergistic efficacy when combined with radiotherapy or anti-CTLA-4 therapy in the EMT6 breast tumor model. These findings suggest that dual modulation of the IL-7 and TGF-β pathways by IL7-TBRII effectively reprograms the immune microenvironment in both primary and metastatic tumors, particularly by promoting CD8+ T cell activation and infiltration, thus offering a promising strategy to improve clinical responses to immunotherapy.

Keywords:  Immunotherapy; Interleukin-7; Recombinant fusion proteins; Transforming growth factor beta

DOI:  https://doi.org/10.4110/in.2025.25.e42
J Clin Invest. 2026 Jan 16. pii: e196722. [Epub ahead of print]136(2):

Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models.

Mengmeng Li, Xiaoya Zhao, Jun Wu, Shimeng Zhou, Yao Fu, Chen Chen, Zhuang Ma, Jiawen Xu, Yun Qian, Zhangding Wang, Bo Wang, Qiang Wang, Qingqing Ding, Changyu Chen, Honggang Wang, Xiaozhong Yang, Weijie Dai, Wenjie Zhang, Shouyu Wang.

  Despite overexpression of N-acetyltransferase 10 (NAT10) in colorectal cancer (CRC), its immunomodulatory role in the tumor microenvironment remains elusive. Here, we reveal that NAT10 promotes immune evasion through N4-acetylcytosine-dependent (ac4C-dependent) mRNA stabilization. Using syngeneic mouse models (MC38/CT-26), intestinal epithelial-cell specific Nat10 conditional KO (Nat10cKO) mice, patient-derived organoids, and clinical specimens, we show that Nat10 ablation enhanced CD8+ T cell-mediated antitumor immunity. Single-cell RNA-seq revealed increased cytotoxic CD8+ T cell infiltration in Nat10cKO tumors, which was corroborated by the inverse correlation of tumoral NAT10 expression and CD8+ T cell number in clinical specimens. Multi-omics integration analysis identified DKK2 as the predominant NAT10-regulated transcript. NAT10 stabilized DKK2 mRNA via ac4C modification, leading to high expression of the DKK2 protein. Secreted DKK2 engaged LRP6 receptors to activate AKT-mTOR signaling, inducing cholesterol accumulation in CD8+ T cells and impairing their cytotoxicity. Pharmacological NAT10 inhibition (Remodelin treatment) or DKK2 neutralization restored CD8+ T cell function and synergized with anti-PD-1 therapy. Our findings establish the NAT10/DKK2/LRP6/AKT-mTOR/cholesterol axis as a critical regulator of CD8+ T cell dysfunction in CRC, positioning NAT10/DKK2 as a potential target to enhance immunotherapy efficacy.

Keywords:  Cancer immunotherapy; Colorectal cancer; Epigenetics; Gastroenterology; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI196722
Oral Oncol. 2026 Jan 12. pii: S1368-8375(26)00002-3. [Epub ahead of print]173 107849

Prognostic significance of p16 and immune cell infiltration in recurrent/metastatic head and neck squamous cell carcinoma treated with PD-1 inhibition: a national DAHANCA cohort study.

Sebastian Søby, Danny Mortensen, Anita Gothelf, Niels Gyldenkerne, Christian Maare, Camilla K Lonkvist, Maria Andersen, Rasmus Kjeldsen, Kasper Toustrup, Trine Tramm, Jesper Grau Eriksen.

  PD-1 inhibition has become an established treatment option for recurrent/metastatic head and neck squamous cell carcinoma (rmHNSCC). However, there is a clear need for improved prognostic tools. This study aimed to identify immune-related tissue biomarkers associated with overall survival (OS) or progression-free survival (PFS) in patients treated with PD-1 inhibition. This national real-world phase IV multicenter retrospective cohort study included Danish patients treated between 2017 and 2023. Pre-treatment biopsies were collected for immunohistochemical analyses. All patients were PD-L1 positive with histologically confirmed rmHNSCC treated with pembrolizumab or nivolumab monotherapy. Biomarker expression was assessed for CD4, CD8, FOXP3, CD20, CD66b, CD68, STING, cGAS, and tumor-infiltrating lymphocytes (TILs), using the median expression as the cut-off value. Formalin-fixed, paraffin-embedded tumor tissue was obtained from 263 eligible patients. Concurrent above median levels of FOXP3 and CD68 were associated with a lower risk of progression (HRPFS: 0.47 [95 % CI: 0.33-0.67]). This interaction appeared to be driven by p16+ oropharyngeal cancers (OPC), where patients with concurrent above median levels of FOXP3 and CD68 showed a median 2-year PFS of 68 % [95 % CI: 42-86] in contrast to those with one or none of the two markers above the median level with a 2-year PFS of 3 % [95 % CI: 0-12] (p < 0.001). In this real-world cohort, a subgroup with a promising prognosis was identified. This subgroup was characterized by p16+ OPC along with concurrent above median levels of FOXP3 and CD68. PD-L1 alone showed no significant association with outcomes.

Keywords:  Biomarker; CD68; FOXP3; PD-L1; Prognostic; rmHNSCC

DOI:  https://doi.org/10.1016/j.oraloncology.2026.107849
J Clin Invest. 2026 Jan 13. pii: e196613. [Epub ahead of print]

T cell receptor-engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models.

Lianghua Shen, Ziyu Chen, Jian Xu, Qiaomei He, Changmeng Zhang, Xiao Zhou, Xiaodan Ding, Jinan Fang, Fanlin Li, Ming Jiao, Yuqin Yang, Baoxia Dong, Liping Wan, Xueying Ding, Yan Zheng, Jingyi Zhou, Chijian Zuo, Tian Min, Ming Zhu, Bin Ma, Yuhua Wan, Qiufang Guo, Hua Zhang, Jian Hua, Pengran Wang, Qi Li, Jiang Long, Xianmin Song, Yan Zhang.

  Malignant tumors with TP53 mutations exhibit poor therapeutic outcomes and high recurrence rates. T cell receptor (TCR)-based T cell therapy shows great promise for targeting intracellular cancer neoantigens. However, the immunogenic potential of TP53 hotspot mutations remain poorly characterized. Here, we identify a immunogenic neoantigen derived from the recurrent TP53R248Q mutation, presented by the prevalent Human Leukocyte Antigen (HLA)-A*11:01 allele. Additionally, we isolated a TP53R248Q reactive TCR that specifically recognize the TP53R248Q mutation without any discernable cross-activity to cognate wild-type TP53 or other TP53 mutants at the same codon position. Functional characterization revealed that TP53R248Q TCR-T cells exhibited selectively cytotoxicity against tumor cells expressing both TP53R248Q mutation and HLA-A*11:01 in vitro. Importantly, the adoptive transfer of TP53R248Q TCR-T cells exhibited significant anti-tumor activity in a clinically relevant patient-derived xenograft (PDX) model engrafted with TP53R248Q/HLA-A*11:01 positive human tumor tissues. Collectively, our study validates the immunogenicity of the TP53R248Q hotspot mutation and provides a TCR with high therapeutic potential for the development of T cell therapies targeting TP53R248Q/HLA-A*11:01 positive cancers.

Keywords:  Cancer immunotherapy; Immunology; Oncology; p53

DOI:  https://doi.org/10.1172/JCI196613
Pediatr Allergy Immunol. 2026 Jan;37(1): e70282

HLA-DR+ CD8+ T lymphocytes as an alternative T-cell activation marker in pediatric HLH: A real-life study.

Clément Triaille, Isabel Fernandez, Fabien Touzot.



Keywords:  CD8+ T lymphocytes; HLA‐DR; T‐cell activation; flow cytometry; hemophagocytic lymphohistiocytosis; pediatric

DOI:  https://doi.org/10.1111/pai.70282
Nature. 2026 Jan 14.

The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction.

Hongcheng Cheng, Yapeng Su, Xiaoli Pan, Yue Xu, Ermei Xie, Jing Du, Daniel G Chen, Xiaomeng Dai, Raphael Gottardo, Philip D Greenberg, Guideng Li.

The multifaceted dysfunction of tumour-infiltrating T cells, including exhaustion and mitochondrial dysfunction, remains a major obstacle in cancer immunotherapy1-6. Transcriptomic and epigenomic regulation of T cell dysfunction have been extensively studied7-9, but the role of proteostasis in regulating these obstacles remains less defined. Here we combined computational analyses of atlases of T cell exhaustion and mitochondrial fitness with performed targeted in vivo CRISPR screens, which identified the E3 ubiquitin ligase KLHL6 as a dual-negative regulator of both T cell exhaustion and mitochondrial dysfunction. Mechanistically, KLHL6 expression promoted TOX poly-ubiquitination and subsequent proteasomal degradation, thereby attenuating the transition of progenitor exhausted T cells towards terminal exhaustion. Simultaneously, KLHL6 maintained mitochondrial fitness by constraining the excessive mitochondrial fission that occurs during chronic T cell receptor stimulation by means of post-translational regulation of the PGAM5-Drp1 axis. However, KLHL6 is naturally downregulated by T cell receptor ligation, mitigating its potentially beneficial ubiquitin ligase activities during exposure to chronic stimulation. Enforcing KLHL6 expression in T cells markedly improved efficacy and long-term persistence against tumours and during viral infections in vivo. These findings uncover KLHL6 as a multifunctional, clinically actionable target for cancer immunotherapy, and highlight the potential of modulating proteostasis and ubiquitin modification to improve immunotherapy.

DOI: https://doi.org/10.1038/s41586-025-09926-8
Oncol Rep. 2026 Mar;pii: 42. [Epub ahead of print]55(3):

Role of tumor‑infiltrating lymphocytes and miR‑155 in breast cancer: Insights into carcinogenesis and their potential as prognostic biomarkers (Review).

Miriam Monteiro Alvares-Vilela, Franciele Schlemmer, Sabrina Simplício De Araújo Romero Ferrari, Mary-Ann Elvina Xavier, Ricardo Titze-De-Almeida.

  <p>Breast cancer is the most common cancer in the female population worldwide. The present review examines the biology of breast cancer, with a focus on the interplay between tumor‑infiltrating lymphocytes (TILs) and microRNAs (miRNAs or miRs). TILs, which reflect the immune system activity in combating tumors, are associated with more favorable prognoses and positive response to therapies. Elevated levels of TILs characterize lymphocyte‑predominant breast cancers (LPBCs), which are associated with higher therapeutic response rates in triple‑negative breast cancer, a type of LPBC. Defining the threshold for LPBCs presents a challenge: TIL levels ≥50% are associated with short‑term pathological complete response as well as long‑term overall and disease‑free survival; however, this percentage is not often achieved in clinical practice. Conversely, a lower threshold of 30% lymphocyte infiltration can predict favorable prognosis for anticancer therapy and allows for the identification of a broader range of patients. The tumor inflammatory landscape is regulated by miRNAs, particularly miR‑155. Elevated levels of miR‑155 are associated with the presence of TILs and a favorable inflammatory profile, leading to a tumor‑inflamed microenvironment. Moreover, miR‑155 is associated with various antitumoral immune cells, including CD8+ T cells and M1 macrophages, but negatively associated with pro‑tumoral regulatory T cells and M2 macrophages. Overexpression of miR‑155 results in an increase in the levels of the C‑X‑C chemokine ligands, constituted by two conserved cysteines separated by a different amino acid which bind to the same chemokine receptor CXC chemokine receptor 3. These results in activation of T cells a process that involves the inhibition of suppressor of cytokine signaling 1 and an elevated ratio of phosphorylated STAT1/STAT3. Additionally, miR‑155 affects key signaling pathways, including the PI3K/AKT and IL‑6/STAT3 pathways, and increases sensitivity to immune checkpoint blockade therapy. In clinical samples from patients with BC, serum levels of miR‑155 align with both tumor miR‑155 levels and the immune status of the tumor. The present review emphasizes the importance of understanding the dynamics between TILs and miRNAs to identify new prognostic and predictive biomarkers, proposing a more integrated and personalized approach in the management of BC.</p>.

Keywords:  biomarker; microRNA‑155; triple‑negative breast cancer; tumor‑infiltrating lymphocyte

DOI:  https://doi.org/10.3892/or.2026.9047
Nat Immunol. 2026 Jan 16.

Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.

Alberto G Conti, Alexander C Evans, Teresa von Linde, Christian Deo T Deguit, Sarah K Whiteside, Alexander J Wesolowski, Charlotte J Imianowski, Yumi Yamashita-Kanemaru, Layla Dahmani, Jack Chapman, Ardon M Pillay, Aws Al-Deka, Randy Greaves, Oliver Burton, Panagiota Vardaka, Shienny Sampurno, Iván Pérez-Núñez, Nicole Y L Saw, Jie Yang, Andrew J M Howden, Klaus Okkenhaug, Suman Mitra, Bartlomiej Swiatczak, Ian A Parish, Rahul Roychoudhuri.

Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.

DOI: https://doi.org/10.1038/s41590-025-02389-z
Oncoimmunology. 2026 Dec 31. 15(1): 2606497

DNA prime and peptide boost immunization elicits robust neoantigen-specific CD8 + T cell responses and therapeutic protection in mouse tumor models.

Pablo Morgado-Cáceres, Francisca Hofmann-Vega, Diego Figueroa, Juan Saavedra-Almarza, Felipe Gálvez-Cancino, Ximena Díaz, Evelyn Menares, Eduardo Roa, Sofia Hidalgo, Manuel Varas-Godoy, Vincenzo Borgna, Alvaro Lladser.

  Therapeutic immunization against tumor neoantigens has the potential to induce potent and highly selective CD8+ T-cell-mediated antitumor immunity. Consequently, immunization strategies that generate robust neoantigen-specific T-cell responses are needed. Here, we tested homologous and heterologous DNA- and peptide-based immunization strategies using a neoantigen model. We observed that priming with DNA followed by peptide boost immunization elicited the strongest CD8+ T-cell responses, which exhibited effector and memory precursor phenotypes and led to the formation of circulating and skin-resident memory T cells. In prophylactic settings, this immunization regimen delayed the growth of B16F10 melanoma and rejected EL4 lymphoma cells expressing a self-antigen. In a therapeutic setting, a DNA prime-peptide boost eliminated EL4 tumors expressing the neo-epitope model in most mice. Consistently, DNA prime-peptide boost targeting two bona fide neoepitopes of MC38 tumor model elicited neoepitope-specific CD8+ T-cell responses and a marked therapeutic effect, which may be enhanced by combining with anti-PD-1 antibody. These results highlight the potential of DNA prime-peptide boost as a promising strategy for therapeutic neoantigen immunization that elicits strong CD8+ T-cell responses and potent antitumor effects.

Keywords:  CD8+ T cells; DNA vaccine; neoantigen; peptide vaccine; therapeutic vaccines; tumor

DOI:  https://doi.org/10.1080/2162402X.2025.2606497
Res Sq. 2026 Jan 07. pii: rs.3.rs-8394722. [Epub ahead of print]

Proteotranscriptomic Dissection of Breast Cancer T Cell States Identifies CD103+ Tfh-derived Cytotoxic Cells Linked to Immunotherapy Response.

Alexander Swarbrick, Ghamdan Al-Eryani, Sophie van der Leij, Etienne Masle-Farquhar, Chia-Ling Chan, Kate Harvey, Sunny Wu, Dan Roden, Taopeng Wang, John Reeves, Bertrand Yeung, Christopher Goodnow, Cindy Ma, Charles Perou, Nir Hacohen, Aziz Al'Khafaji, Mats Nilsson, Joakim Lundeberg, Marcel Batten, Simon Junankar.

While cancer immunotherapies have primarily focused on activation of cytotoxic CD8 cells, CD4 T cell activity is also associated with survival and immunotherapeutic response in numerous cancers. We applied integrated single-cell RNA sequencing and multiplexed protein epitope profiling to breast cancer samples to resolve the complexity of immune cell states within the tumor microenvironment. This approach enhanced phenotypic resolution, identifying three distinct states within the CD4 T follicular helper-like (Tfh) cell cluster. A CXCR4high progenitor state gave rise to two differentiated states: an IGFL2high subset resembling conventional Tfh cells and localised to B cell-rich lymphoid aggregates, and a CD103+ subset, exhibiting features of tissue residency, exhaustion, and cytotoxicity, which co-localised with tumor foci. CD103+ Tfh-like cells were found to interact with CXCL10+ macrophages through production of CCL chemokines and CSF1. A higher CD103+ Tfh to IGFL2high Tfh ratio, together with the selective clonal expansion of the CD103+ subset, was strongly associated with improved tumour immunity and superior responses to anti-PD-1 checkpoint blockade, surpassing the predictive value of exhausted CD8 T cells. These findings integrate Tfh and CD4 with cytotoxic potential in breast cancer, offering new insight into anti-tumor immunity and response to checkpoint blockade.

DOI: https://doi.org/10.21203/rs.3.rs-8394722/v1
Nat Immunol. 2026 Jan 16.

BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells.

Taidou Hu, Ziang Zhu, Ying Luo, Safuwra Wizzard, Jonathan Hoar, Sejal S Shinde, Kiddist Yihunie, Chen Yao, Tuoqi Wu.

Stem-like T cells promote the efficacy of immunotherapy and are heterogeneous in stemness, with long-term (LT) stem-like T cells at the apex of this hierarchy. How the stemness hierarchy is regulated in chimeric antigen receptor (CAR) T cells and how it affects antitumor function are unclear. Here we show that BACH2 dose-dependently regulates LT stem-like differentiation and antitumor immunity of CAR T cells. LT stem-like CAR T cells that appear before infusion and re-emerge after tumor clearance have superior antitumor immunity and the greatest BACH2 expression. BACH2 promotes the antitumor response of CAR T cells and the LT stem-like transcriptional program. Temporal and quantitative induction of BACH2 expression in CAR T cells during manufacturing using chemical switches fine-tunes the degree of stemness and imprints greater control of solid tumors. Together, these data show that BACH2 dosage defines stemness hierarchy in CAR T cells and can be temporally and tunably controlled to optimize differentiation and antitumor efficacy.

DOI: https://doi.org/10.1038/s41590-025-02388-0
J Immunother Cancer. 2026 Jan 12. pii: e013317. [Epub ahead of print]14(1):

Fully human anti-B7-H4 antibody induces lysosome-dependent ferroptosis to reverse primary resistance to PD-1 blockade.

Renlu Zhang, Yang Wang, Yue Wu, Bingyu Zheng, Qiumei Cao, Yunhan Chen, Zhengyun Cao, Yanyang Zhu, Linlin Zhou, Qiuyu Zhang.

   BACKGROUND: Although immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with certain cancers, their efficacy is largely confined to "hot" tumors characterized by robust infiltration of tumor-specific CD8+ T cells. Conversely, tumors expressing B7-H4 often exhibit an immunologically "cold" tumor microenvironment with poor T cell infiltration, contributing to primary resistance to programmed cell death protein 1 (PD-1) blockade.
METHODS: We evaluated the association between B7-H4 expression and clinical outcomes in ICI-treated patients using public immunotherapy datasets. The role of B7-H4 in mediating resistance to PD-1 therapy was examined in mouse tumor models. A fully human anti-B7-H4 monoclonal antibody (clone A8) was generated via phage display screening from a non-immunized human single-chain variable fragment library. In vitro assays assessed antibody-induced tumor cell death and immune activation, while in vivo efficacy was tested in MC38-mH4 and SKOV3-hH4 tumor models, as well as human colorectal cancer organoids. Statistical analyses included Student's t-test, one-way analysis of variance, and Kaplan-Meier survival analysis, with p<0.05 considered significant.
RESULTS: High B7-H4 expression was associated with inferior prognosis in patients receiving ICI therapy. In MC38-mH4 tumors, B7-H4 expression conferred resistance to anti-PD-1 treatment. We identified A8, a novel antibody targeting the IgV-like domain of B7-H4, with cross-reactivity to both human and mouse B7-H4. A8-hIgG1 and its Fab fragment induced dynamin-dependent endocytosis of B7-H4, resulting in lysosomal accumulation, altered lysosomal membrane permeabilization and intracellular acidification, ultimately triggering ferroptosis, a form of immunogenic cell death. A8 binding was enhanced under acidic conditions (pH 5.5), promoting lysosome-dependent degradation of B7-H4. A8-induced ferroptosis enhanced dendritic cell maturation, macrophage phagocytosis, and T cell activation. In vivo, A8 promoted CD8+ T cell and HER2 chimeric antigen receptor-T cell infiltration, inhibited tumor growth, and synergized with PD-1 blockade to overcome primary resistance in multiple preclinical models. This immunogenic and lysosome-dependent cell death mechanism was unique to A8 among the anti-B7-H4 antibodies tested.
CONCLUSIONS: Our study identifies a novel mechanism by which a fully human anti-B7-H4 antibody induces lysosome-dependent immunogenic tumor cell death. These findings support the therapeutic potential of A8 as a single agent or in combination with PD-1 blockade to overcome immune resistance in B7-H4-expressing "cold" tumors.

Keywords:  Combination therapy; Immune Checkpoint Inhibitor; Monoclonal antibody; T cell; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-013317