bims-tuinly 2025-04-13 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–04–13
twenty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor-infiltrating lymphocyte immunotherapy comes of age: a journey of development in the Surgery Branch, NCI.
The prognostic impact of tumor mutations and tumor-infiltrating lymphocytes in patients with localized pMMR colorectal cancer - A systematic review and meta-analysis.
Safety of adoptive therapy with tumor-infiltrating lymphocytes and high-dose recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.
CD40L stimulates tumor-infiltrating B-cells and improves ex vivo TIL expansion.
Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.
Pembrolizumab in Patients with Advanced Miscellaneous Rare Cancers: Results from a Phase 2 Basket Trial.
Tumor-specific CXCR6 positive precursor CD8+ T cells mediate tumor control in metastatic melanoma.
APOBEC Driven Hypermutation in the Lymphocyte-Predominant Group of Triple-Negative Breast Cancer.
First-in-Human Clinical Trial of Vaccination with WDVAX, a Dendritic Cell Activating Scaffold Incorporating Autologous Tumor Cell Lysate, in Metastatic Melanoma Patients.
Screening and mechanistic study of natural compounds that enhance T cell anti-tumor effects post-heat treatment.
Serum carcinoembryonic antigen levels as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with colorectal cancer.
Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors.
Pipelines for lymphocyte homeostasis maintenance during cancer immunotherapy.
Integrating inflammation, nutrition, and immunity: the CALLY index as a prognostic tool in digestive system cancers - a systematic review and meta-analysis.
Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial.
Exploiting regulatory T cells (Tregs): Cutting-edge therapy for autoimmune diseases.
Protocol to profile tumor and microenvironment from ovarian cancer patient samples and evaluate cell-based therapy using in vitro killing assays.
The role of the Androgen Receptor (AR) in endometrial cancer aggressiveness: Correlation with other prognostic markers and therapeutic implications. A retrospective observational study.
Assessment of antigen immunogenicity formulated in minigenes transfected into antigen-presenting cells.
Single-cell and spatial transcriptomic analyses revealing tumor microenvironment remodeling after neoadjuvant chemoimmunotherapy in non-small cell lung cancer.
Evaluation of clinical and immunological responses to recombinant canine interleukin-15 therapy in dogs with cancer: A pilot study.
A tumor-infiltrating B lymphocytes -related index based on machine-learning predicts prognosis and immunotherapy response in lung adenocarcinoma.
Revealing tumor microenvironment communication through m6A single-cell analysis and elucidating immunotherapeutic potentials for cutaneous melanoma (CM).
Pre-existing intratumoral stem-like CD8+ T cells drive radiotherapy-induced tumor immunity.
The spontaneous neoantigen-specific CD4 + T cell response to a growing tumor is functionally and phenotypically diverse.
Tertiary Lymphoid Structures Correlate With Better Prognosis in Patients With Retroperitoneal Sarcoma: A Retrospective Study.

J Immunother Cancer. 2025 Apr 09. pii: e011734. [Epub ahead of print]13(4):

Tumor-infiltrating lymphocyte immunotherapy comes of age: a journey of development in the Surgery Branch, NCI.

Stephanie L Goff, Steven A Rosenberg.

  The early development of tumor-infiltrating lymphocytes into an effective clinical strategy was fundamentally the work of hundreds of scientists and clinicians within the Surgery Branch of the National Cancer Institute under the leadership of Steven Rosenberg. That journey brought new insights into the tumor-immune cell interface and ultimately helped create a new first-in-class therapeutic for patients with metastatic cancer.

Keywords:  Adoptive cell therapy - ACT; Cytokine; Immunotherapy; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2025-011734
Crit Rev Oncol Hematol. 2025 Apr 04. pii: S1040-8428(25)00102-7. [Epub ahead of print]211 104714

The prognostic impact of tumor mutations and tumor-infiltrating lymphocytes in patients with localized pMMR colorectal cancer - A systematic review and meta-analysis.

Amalie Thomsen Nielsen, Ida Kolukisa Saqi, Tobias Freyberg Justesen, Michael Tvilling Madsen, Ismail Gögenur, Adile Orhan.

   BACKGROUND: Tumor mutations and the composition of the tumor microenvironment have prognostic and therapeutic significance in colorectal cancer (CRC). However, immunotherapy remains a challenge for patients with proficient mismatch repair (pMMR) CRC. In this paper, the association between tumor-infiltrating lymphocytes (TILs) and tumor mutations on survival outcomes in patients with localized pMMR CRC was examined.
METHODS: A systematic review of the literature and a meta-analysis were conducted in accordance with the PRISMA guidelines. The literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The outcomes of interest were overall survival, disease-free survival, and cancer-specific survival. The risk of bias was assessed through the Newcastle-Ottawa Scale and the quality of the cumulative evidence was evaluated through the modified GRADE approach.
FINDINGS: In total, 8498 articles were screened for eligibility and 44 articles were included in the meta-analysis with 33,704 patients in total. Patients with high infiltration of any TILs showed significantly improved overall survival (HR = 0.57, 95 % CI: 0.49-0.67, I2: 0 %), especially for the subgroup of CD3 + (HR = 0.52, 95 % CI: 0.38-0.71, I2: 0 %) and CD8 + (HR = 0.60, 95 % CI: 0.37-0.99, I2: 10 %) TILs. Patients with BRAF mutation (HR = 2.68, 95 % CI: 1.47-4.89, I2: 83 %) and KRAS mutation (HR = 1.25, 95 % CI: 1.18-1.33, I2: 0 %) showed decreased overall survival.
INTERPRETATION: High infiltration of TILs, especially CD3 + and CD8 + , was associated with significantly improved survival, while BRAF and KRAS mutations were correlated with worse survival outcomes for patients with non-metastatic pMMR CRC.

Keywords:  BRAF; Colorectal cancer; KRAS; Proficient mismatch repair; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104714
Ann Oncol. 2025 Apr 08. pii: S0923-7534(25)00135-8. [Epub ahead of print]

Safety of adoptive therapy with tumor-infiltrating lymphocytes and high-dose recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.

S Martín-Lluesma, U Dafni, K Vervita, D Karlis, G Dimopoulou, Z Tsourti, G Villacampa, V Galvao, J Lostes, E Muñoz-Couselo, M Rotxés, X Villalobos, S Muñoz, J B A G Haanen, I M Svane, J M Piulats, J Martin-Liberal, A Gros, G Coukos, E Garralda.

   BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has consistently shown efficacy in advanced melanoma. Its combination with non-myeloablative but lymphodepleting (NMA-LD) chemotherapy and high-dose interleukin-2 (HD-IL-2) inevitably lead to severe treatment-related adverse events. The systematic recording of the observed toxicities, which is the aim of the present meta-analysis, will further enhance the implementation and management of this treatment schema.
METHODS: A comprehensive search was conducted in PubMed up to 29 February 2024. In this meta-analysis we focused on studies of treatment-refractory advanced cutaneous melanoma with TILs administered in combination with NMA-LD chemotherapy and HD-IL-2 (≥600,000 IU/kg). Our primary endpoint was severe adverse events (AEs) of grade 3 or higher. The safety data was consistently coded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Findings are synthesized using tables, while pooled estimates for groups of AEs of particular interest are derived from random effect models.
RESULTS: A total of 12 HD-IL-2 studies, of 670 patients, with available toxicity information were included in this meta-analysis. Blood toxicities were identified as the most common AEs. In the frame of the formal meta-analysis the pooled estimate of the probability of febrile neutropenia was 60% (95%CI: 36%-83%). The total pooled estimate for the probability of severe "immunologic reaction" events, was 4% (95% CI: 1%- 6%), while the respective probability for experiencing a severe AE in MedDRA SOC category 'Infections and infestations' was 8% (95% CI: 4%- 11%). In addition, in total, 9 fatal (grade 5) AEs have been reported, mostly stated as not attributed to the treatment or attributed to NMA/HD-IL-2.
CONCLUSIONS: TIL-ACT, a new approved and promising therapy for melanoma patients, presents a distinctive toxicity profile that is currently manageable with supportive care methods, with reported toxicities mainly arising from NMA-LD chemotherapy and HD-IL-2, and a low risk of severe immunologic reaction events. Continued systematic recording and publication of adverse events, even the rare ones, and its relation to treatment components, are essential to move the field forward.

Keywords:  adoptive cell therapy (ACT); advanced melanoma; meta-analysis; safety; tumor-infiltrating lymphocytes (TIL)

DOI:  https://doi.org/10.1016/j.annonc.2025.04.001
J Immunother Cancer. 2025 Apr 08. pii: e011066. [Epub ahead of print]13(4):

CD40L stimulates tumor-infiltrating B-cells and improves ex vivo TIL expansion.

Renata Ariza Marques Rossetti, Leticia Tordesillas, Matthew S Beatty, Junior Cianne, Elena Martinez Planes, Dongliang Du, Sebastian Snedal, Chao Wang, Bradford A Perez, Anders Berglund, Yian Ann Chen, Amod Sarnaik, James J Mulé, Benjamin Creelan, Shari Pilon-Thomas, Daniel Abate-Daga.

   BACKGROUND: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is now a Food and Drug Administration (FDA)-approved treatment for melanoma. While this is a major milestone, there is room for improvement to increase clinical response rates and to further optimize the manufacturing of TIL products. In this study, we characterized the association of tumor-infiltrating B-cells (TIL-B) and tertiary lymphoid structures (TLSs) with clinical response to TIL therapy and tested whether the presence of B-cells in the tumor can be leveraged to optimize TIL manufacture.
METHODS: Tumor sections from TIL responders (R, n=9) and non-responders (NR, n=11) were analyzed by RNA sequencing, and immune cell content was estimated in silico. To study the association between B-cells and TIL expansion, we quantified B-cell subsets and TIL phenotype by flow cytometry. CD40L-induced effects on melanoma-infiltrating B-cells were analyzed by flow cytometry and scRNA-sequencing.
RESULTS: Tumors from TIL clinical responders had greater abundance of class-switched B-cells (p=0.007) and a greater TLS score (p=0.03) than those of NRs. In addition, greater abundance of B-cells (p≤0.05) and switched memory B-cells (CD27+ IgD-, p≤0.05) in the tumors were associated with greater TIL expansion. Stimulation of TIL-B through addition of CD40L during TIL ex vivo culture improved their expansion success rate from 33% to 67% (p=0.03). Similarly, the addition of CD40L to non-small cell lung cancer (NSCLC) TIL cultures shortened the manufacturing period by 1 week. Moreover, CD40L-enhanced TIL showed more stem-like T-cells (CD39- CD69-, p≤0.05) and an enrichment of neoantigen-reactive T-cell clones in NSCLC TIL. Gene expression analysis showed that CD40L induced gene expression changes in TIL-B after 48 hours in culture (126 differentially expressed genes (DEGs)), with minimal to no changes observed in other immune cell types (including 12 DEG in macrophages, 10 DEG in dendritic cells, and none in monocytes). B-cell DEGs included upregulated co-stimulatory ligands (CD83, CD58), chemokines (CCL22, CCL17), among others. CD40L-induced upregulation of CD58 by melanoma infiltrating B-cells was associated with successful TIL expansion.
CONCLUSIONS: Our results show that CD40L-stimulated B-cells can be leveraged to enhance the quality and quantity of TIL. Clinical trial NCT05681780 is currently testing this concept applied to NSCLC TIL.

Keywords:  Adoptive cell therapy - ACT; B cell; Melanoma; Non-Small Cell Lung Cancer; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2024-011066
Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00188-1. [Epub ahead of print]85(7): 1258-1259

Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.

Maria T Diaz-Meco, Juan F Linares, Jorge Moscat.

Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.

DOI: https://doi.org/10.1016/j.molcel.2025.02.026
J Immunother Precis Oncol. 2025 May;8(2): 143-151

Pembrolizumab in Patients with Advanced Miscellaneous Rare Cancers: Results from a Phase 2 Basket Trial.

Mirella Nardo, Camila Braganca Xavier, Bettzy Stephen, Jeffrey A How, Justin Moyers, Vivek Subbiah, David S Hong, Aung Naing.

   Introduction: Rare solid tumors account for one-quarter of cancers among adults in the United States, but few resources have been devoted to their treatment. We evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with rare solid tumors.
Methods: We conducted a phase 2 basket trial that included patients with rare, advanced tumors. Patients were enrolled in the study in nine tumor-specific and a 10th cohort of miscellaneous rare histologies. Patients received pembrolizumab 200 mg intravenously every 21 days. The primary endpoint was the non-progression rate at 27 weeks per immune-related Response Evaluation Criteria in Solid Tumors (RECIST). The secondary endpoints were confirmed objective response (immune-related complete response [irCR] or partial response [irPR]), clinical benefit (irCR, irPR, or immune-related stable disease [irSD] ≥ 4 months), safety, and tolerability. Pretreatment biopsy specimens were examined for programmed cell death ligand-1 combined positive score (CPS) and tumor-infiltrating lymphocyte status. Herein, we report the outcomes in 12 patients with miscellaneous rare histologies who were on the study between October 5, 2016, and August 30, 2019.
Results: Twelve patients with rare cancers were enrolled from October 5, 2016, to August 30, 2019. The patients received a median of four lines of therapy before enrollment. Three patients (25%) remained free of progression at 27 weeks, one patient (8%) had an objective response, and five patients (42%) received clinical benefit. Six patients (50%) experienced at least one adverse event, of whom five (42%) experienced immune-related adverse events. The only grade ≥ 3 adverse event was non-immune-related anemia. Among the seven patients with CPS ≥ 1, one had irPR and two had irSD as the best response. Among the six patients with a CPS of 3, one had irPR and two had irSD as the best response.
Conclusions: Single-agent pembrolizumab showed modest efficacy and was well tolerated in patients with rare solid tumors (ClinicalTrials.gov Identifier: NCT02721732).

Keywords:  cancer; immunotherapy; investigational; rare tumors; therapies

DOI:  https://doi.org/10.36401/JIPO-24-27
Cell Oncol (Dordr). 2025 Apr 07.

Tumor-specific CXCR6 positive precursor CD8+ T cells mediate tumor control in metastatic melanoma.

Yang Song, Ji Chen, Yaqin Zhang, Ning Wu, Yongjun Zhu, Gang Chen, Feng Miao, Zhiming Chen, Yiqing Wang.

   BACKGROUND: Adoptive cell therapy (ACT) mediates durable and complete regression of various cancers. However, its efficacy is limited by the long-term persistence of cytotoxic T lymphocytes, given their irreversible dysfunction within the tumor microenvironment. Herein, we aimed to establish an artificial lung metastasis model to examine T-lymphocyte subsets, in order to identify potential effective cell subsets for ACT.
METHODS: A metastatic lung melanoma mouse model was established using OVA-expressing melanoma B16 cells. Flow cytometry analysis was conducted to examine the surface markers, transcription factors, and secreted cytokines of tumor-specific CD8+ T cells within metastatic tissues. The infiltrated cells were sorted by flow cytometry for in vitro tumor cell killing assays or in vivo cell infusion therapy combined with chemotherapeutic drugs and immune checkpoint blockade antibodies.
RESULTS: Exhausted CD8+ T cells (Tex) exhibited high heterogeneity in metastatic tissues. Among Tex cells, the CXCR6- precursor cell showed certain memory characteristics, including phenotype, transcription factors, and maintenance, whereas the CXCR6+ subpopulation partially lost these traits. Moreover, CXCR6+ precursor cells effectively replenished effector-like Tex cells in metastatic tissues and exerted direct cytotoxicity against tumor cells. Notably, transferring these tumor-specific CXCR6+ precursor-exhausted T (Texp) cells into recipients induced a substantial regression of metastasis. In addition, these cells could respond to immune checkpoint blockade, which could better control tumor metastasis.
CONCLUSIONS: In our study, a subset of antigen-specific CXCR6-expressing Texp cells was observed within the metastatic tissue. The cells served as a crucial source of effector-like Tex cells and exerted direct cytotoxic effects on tumor cells. Adoptive transfer of CXCR6+ Texp cells effectively mitigated lung metastasis in mice. This study helps elucidate the role of Texp cells in metastasis, thereby offering novel insights into enhancing the efficacy and durability of immunotherapy.

Keywords:  CXCR6+precursor exhausted T cell; Immunotherapy; Metastasis; Tumor-specific

DOI:  https://doi.org/10.1007/s13402-025-01040-1
Lab Invest. 2025 Apr 06. pii: S0023-6837(25)00075-3. [Epub ahead of print] 104165

APOBEC Driven Hypermutation in the Lymphocyte-Predominant Group of Triple-Negative Breast Cancer.

Miseon Lee, Ahwon Lee, Tae-Kyung Yoo, Byung Joo Chae, Sung Gwe Ahn, Byung-Ock Choi, Woo-Chan Park, Sung Hun Kim, Jieun Lee, Jun Kang.

  This study aimed to evaluate the clinicopathologic and genomic characteristics of triple-negative breast cancer (TNBC) subclassification. TNBC was classified into the luminal androgen receptor (LAR) subtype and the tumor-infiltrating lymphocytes (TILs) groups of the non-LAR subtype-lymphocyte-predominant (LP), lymphocyte-intermediate (LI), and lymphocyte-depleted (LD)-based on androgen receptor immunohistochemistry and TILs. Clinicopathologic and genomic characteristics were evaluated for these TNBC subclasses. The LP group was associated with a histologic type of carcinoma with medullary features, a higher tumor mutation burden, and increased APOBEC activity, indicative of APOBEC-driven hypermutation. The LAR subtype was characterized by a higher prevalence of PIK3CA mutations, lower homologous recombination deficiency scores, and associations with histologic types of invasive lobular carcinoma, and carcinoma with apocrine differentiation. This study demonstrates the distinct clinicopathologic and genomic characteristics of TNBC subclassifications. APOBEC activity-related hypermutation is a defining characteristic of the LP group.

Keywords:  APOBEC Activity; Hypermutation; Triple-Negative Breast Cancer; Tumor-Infiltrating Lymphocytes; Whole-Exome Sequencing

DOI:  https://doi.org/10.1016/j.labinv.2025.104165
Cancer Immunol Res. 2025 Apr 11.

First-in-Human Clinical Trial of Vaccination with WDVAX, a Dendritic Cell Activating Scaffold Incorporating Autologous Tumor Cell Lysate, in Metastatic Melanoma Patients.

F Stephen Hodi, Anita Giobbie-Hurder, Kwasi Adu-Berchie, Srin Ranasinghe, Ana Lako, Mariano Severgnini, Emily M Thrash, Jason L Weirather, Joanna Baginska, Michael P Manos, Edward J Doherty, Alexander Stafford, Heather Daley, Jerome Ritz, Patrick A Ott, Kathleen L Pfaff, Scott J Rodig, Charles H Yoon, Glenn Dranoff, David J Mooney.

The optimal means to prime for effective anti-tumor immunity in a cancer patient remains elusive in the current era of checkpoint blockade. Crafting a strategy to amplify CD8+ T cells while blocking regulatory cells should increase immunotherapy efficacy. Biomaterial carriers have been demonstrated in preclinical studies to amplify the effects of immunomodulatory agents, synergistically integrate the effects of different agents, and concentrate and manipulate immune cells in vivo. In this phase I trial in patients with metastatic melanoma, the cytokine GM-CSF and the innate TLR9 agonist CpG oligonucleotide were admixed with autologous tumor lysate onto a microporous poly-lactide-co-glycolide (PLG) matrix polymer scaffold that achieves precise control over the spatial and temporal release of immunostimulatory agents in vivo. This materials system served as a physical antigen-presenting structure for which dendritic cells and other immune-stimulating cells are recruited and activated (WDVAX). In this first clinical trial of a macroscale biomaterial-based vaccine, WDVAX treatment was found to be feasible and induced immune activation in melanoma patients.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0333
Front Immunol. 2025 ;16 1537398

Screening and mechanistic study of natural compounds that enhance T cell anti-tumor effects post-heat treatment.

Zhaoyi Wang, Zhongqi Diao, Yiyan Zhang, Jiangying Liu, Yeshan Li, Zijin Sun, Huimin Zhen, Haojia Wang, Siyun Yang, Tieshan Wang, Lei Ni.

   Introduction: Following the approval of Chimeric Antigen Receptor T-cell Immunotherapy(CAR-T) in multiple countries, the Food and Drug Administration (FDA) approved tumor-infiltrating lymphocytes (TILs) and T-cell receptor-engineered T cells (TCR-T) treatments this year. The utilization of adoptive immunotherapy in tumor treatment has become increasingly prominent. Optimizing the cytotoxic effects of immune cells under in vitro culture conditions represents a current hot research topic in this domain.
Methods: In the current experiment, we conducted in vitro heat treatment on Jurkat-derived T cells at 39°C. On this basis, we utilized nine distinct injectable solutions and over 70 monomer components of Traditional Chinese Medicine (TCM). Subsequently, we co-cultured these treated Jurkat cells with K562-eGFP cells, and the co-culture process was monitored in real-time using the IncuCyte live-cell analysis system. Equally important, we combined HiMAP high-throughput transcriptome sequencing, proteomics, and metabolomics for in-depth examination. We screened for compounds possessing anti-tumor properties and thoroughly investigated their mechanisms of action.
Results and Discussion: The findings indicated that heating treatment augmented the cytotoxic effect of Jurkat cells against malignant tumors, and the optimal effect was achieved when T cells were exposed to 39°C for a duration of 24 hours(48% increase in cell proliferation rate compared to 37°C treatment). By triggering the generation of heat shock proteins and facilitating mitochondrial energy supply, the 39°C treatment amplified the anti-tumor functions of T cells. By analyzing the data, we identified 3 injectable solutions and more than 20 effective monomers capable of further enhancing the tumor-killing ability of T cells. High-throughput transcriptomics studies disclosed that the combination of thermotherapy and TCM promoted Jurkat cell proliferation, activation, and cytotoxic functions of Jurkat cells, thereby activating the Regulation of mitotic cell cycle to exert anti-tumor effects. The integration of transcriptomic and proteomic data demonstrated that Shengmai Injection significantly enhances the tumor-killing effect of Jurkat cells by down-regulating the Regulation of Apoptosis and Regulation of mitotic cell cycle signaling pathways.

Keywords:  Chinese medicine; RNA-Seq; adoptive cell therapy; enhance immunity; proteomics; temperature; untargeted metabolomics

DOI:  https://doi.org/10.3389/fimmu.2025.1537398
J Immunol. 2025 Apr 09. pii: vkaf037. [Epub ahead of print]

Serum carcinoembryonic antigen levels as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with colorectal cancer.

Jieyao Li, Dan Wang, Zhen Zhang, Kai Sun, Qingyang Lei, Xuan Zhao, Jianmin Huang, Liping Wang, Yi Zhang.

  Cytokine-induced killer (CIK) cells, as an adoptive immunotherapy, are effective at treating colorectal cancer (CRC). However, whether an individual can benefit from CIK cell therapy remains unclear. In this study, we analyzed the long-term effects of CIK cell therapy and specifically the relationship between tumor-associated antigen expression and the survival benefit of CIK cell therapy in patients with CRC. We conducted a retrospective clinical study of 98 patients with CRC who were pathologically diagnosed between 2010 and 2014. Of the patients in the study, 48 received surgery and/or chemotherapy (control group), and 50 received CIK cell infusion with chemotherapy or surgery (CIK group). CIK cells exhibited significant antitumor activity, expressing high levels of CD107 and increasing the apoptosis of CRC cells in vitro. Survival analysis showed that adjuvant CIK cell immunotherapy improved overall survival (OS) and progression-free survival (PFS) of patients with CRC. Moreover, OS and PFS improved significantly, irrespective of the stage of the disease. Furthermore, CIK cell adjuvant therapy significantly increased OS and PFS in patients with carcinoembryonic antigen (CEA) levels lower than 5 ng/ml before surgery, but not in patients with CEA levels above 5 ng/ml. Univariate and multivariate analyses showed that CEA expression is an independent prognostic factor for OS and PFS in the CIK cell treatment group. Adjuvant CIK cell therapy is an effective strategy for prolonging OS and PFS in patients with CRC, especially in those with serum CEA levels below 5 ng/ml.

Keywords:  CEA; CIK; colorectal cancer; immunotherapy; prognosis

DOI:  https://doi.org/10.1093/jimmun/vkaf037
J Immunother Cancer. 2025 Apr 05. pii: e010237. [Epub ahead of print]13(4):

Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors.

Xiangyun Niu, Pengchao Zhang, Liujiang Dai, Xixia Peng, Zhongming Liu, Yexiao Tang, Guizhong Zhang, Xiaochun Wan.

   BACKGROUND: Adoptive cell therapy using genetically engineered chimeric antigen receptor (CAR)-T cells is a new type of immunotherapy that directs T cells to target cancer specifically. Although CAR-T therapy has achieved significant clinical efficacy in treating hematologic malignancies, its therapeutic benefit in solid tumors is impeded by the immunosuppressive tumor microenvironment (TME). Therefore, we sought to remodel the TME by activating tumor-infiltrating immune cells to enhance the antitumor function of CAR-T cells.
METHODS: We engineered CAR-T cells expressing Salmonella flagellin (Fla), a ligand for toll-like receptor 5, to activate immune cells and reshape the TME in solid tumors. Functional validation of the novel Fla-engineered CAR-T cells was performed in co-cultures and mouse tumor models.
RESULTS: Fla could activate tumor-associated macrophages and dendritic cells, reshaping the TME to establish an "immune-hot" milieu. Notably, this "cold" to "hot" evolution not only improved CAR-T cell function for better control of target-positive tumors, but also encouraged the production of endogenous cytotoxic CD8+T cells, which targeted more tumor-associated antigens and were thus more effective against tumors with antigenic heterogeneity.
CONCLUSION: Our study reveals the potential and cellular mechanisms for Fla to rewire antitumor immunity. It also implies that modifying CAR-T cells to express Fla is a viable strategy to improve the efficacy of CAR-T cell treatment against solid tumors.

Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Solid tumor; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-010237
Front Immunol. 2025 ;16 1522417

Pipelines for lymphocyte homeostasis maintenance during cancer immunotherapy.

Bensu Du, Jin Geng, Bin Wu, Houru Wang, Ru Luo, Hanmeng Liu, Rui Zhang, Fengping Shan, Lei Liu, Shuling Zhang.

  In general, increasing lymphocyte entry into tumor microenvironment (TME) and limiting their efflux will have a positive effect on the efficacy of immunotherapy. Current studies suggest maintenance lymphocyte homeostasis during cancer immunotherapy through the two pipelines tumor-associated high endothelial venules and lymphatic vessels. Tumor-associated high endothelial venules (TA-HEVs) play a key role in cancer immunotherapy through facilitating lymphocyte trafficking to the tumor. While tumor-associated lymphatic vessels, in contrast, may promote the egress of lymphocytes and restrict their function. Therefore, the two traffic control points might be potential to maintain lymphocyte homeostasis in cancer during immunotherapy. Herein, we highlight the unexpected roles of lymphocyte circulation regulated by the two gateways for through reviewing the biological characters and functions of TA-HEVs and tumor-associated lymphatic vessels in the entry, positioning and exit of lymphocyte cells in TME during anti-tumor immunity.

Keywords:  CD8 + T cells; immunotherapy; lymphocytes; tumor-associated high endothelial venules; tumor-associated lymphatic vessels

DOI:  https://doi.org/10.3389/fimmu.2025.1522417
BMC Cancer. 2025 Apr 11. 25(1): 672

Integrating inflammation, nutrition, and immunity: the CALLY index as a prognostic tool in digestive system cancers - a systematic review and meta-analysis.

Bo Wu, Jingting Liu, Chaodan Shao, Dongli Yu, Jianhua Liao.

   BACKGROUND: Digestive system cancers remain a leading cause of cancer-related mortality globally, underscoring the need for reliable prognostic tools. The C-reactive protein-Albumin-Lymphocyte (CALLY) index, which reflects inflammation, nutrition, and immunity, has shown potential in predicting survival. However, comprehensive evaluations of its role in digestive system cancers are still limited.
METHODS: A meta-analysis of English-language studies from online databases was performed to assess the prognostic value of the CALLY index. Pooled hazard ratios (HRs) were calculated for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), and cancer-specific survival (CSS).
RESULTS: A total of eighteen articles (19 studies, encompassing 7,951 patients) were included. A lower CALLY index was significantly associated with poorer outcomes across all survival endpoints. The pooled HR for OS was 1.973 (95% CI: 1.734-2.244), with HRs for DFS, RFS, and CSS being 2.093 (95% CI: 1.682-2.604), 1.462 (95% CI: 1.292-1.654), and 2.456 (95% CI: 1.887-3.221), respectively (all P < 0.001). Subgroup analyses for OS demonstrated consistent prognostic significance across various treatment strategies, cancer types, cutoff values, sample sizes, and regions. Notably, the CALLY index was a strong predictor of OS in surgical patients (HR = 2.014, 95% CI: 1.794-2.260, P < 0.001). Sensitivity analyses validated the robustness of these findings, with minimal publication bias (Egger's test P = 0.053).
CONCLUSIONS: The CALLY index serves as a cost-effective and reliable biomarker for predicting prognosis in digestive system cancers. Its utility as a pre-treatment risk stratification tool, which integrates key factors of inflammation, nutrition, and immunity, renders it valuable for guiding clinical decision-making.

Keywords:  CALLY index; Digestive system cancers; Meta-analysis; Prognostic biomarker

DOI:  https://doi.org/10.1186/s12885-025-14074-3
Nat Med. 2025 Apr 09.

Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial.

Martin Wermke, Dejka M Araurjo, Manik Chatterjee, Apostolia M Tsimberidou, Tobias A W Holderried, Amir A Jazaeri, Ran Reshef, Carsten Bokemeyer, Winfried Alsdorf, Katrin Wetzko, Peter Brossart, Katrin Aslan, Linus Backert, Sebastian Bunk, Jens Fritsche, Swapna Gulde, Silvana Hengler, Norbert Hilf, Mohammad B Hossain, Jens Hukelmann, Mamta Kalra, Delfi Krishna, M Alper Kursunel, Dominik Maurer, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Karine Pozo, Arun Satelli, Marilena Letizia, Heiko Schuster, Oliver Schoor, Claudia Wagner, Hans-Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja, Steffen Walter, Toni Weinschenk, Jason J Luke, Cedrik M Britten.

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .

DOI: https://doi.org/10.1038/s41591-025-03650-6
Int Immunopharmacol. 2025 Apr 10. pii: S1567-5769(25)00614-9. [Epub ahead of print]155 114624

Exploiting regulatory T cells (Tregs): Cutting-edge therapy for autoimmune diseases.

Marwa Hassan, Mohamed Elzallat, Dina Mostafa Mohammed, Mahmoud Balata, Walaa H El-Maadawy.

  Regulatory T cells (Tregs) are a specialized subset of suppressive T cells that are essential for maintaining self-tolerance, regulating effector T cells, managing microbial infections, preventing tumors, allergies, and autoimmune disorders, and facilitating allograft transplantation. Disruptions in Treg function or abundance contribute to an imbalance between pathogenic and protective immune cells in autoimmune diseases. Recently, one promising treatment strategy to restore immune balance involves the selective expansion or manipulation of Tregs using low-dose IL-2 therapy, adoptive Treg cell transfer, and chimeric antigen receptor (CAR)-Treg approaches. Tregs have been shown in an increasing number of research studies to prevent or even treat a variety of disorders, such as tumors, autoimmune and allergic diseases, transplant rejection, and graft-versus-host disease. A thorough comprehension of Treg function is anticipated to provide clear prospects for effective Treg immunotherapy in the treatment of a wide range of diseases. This review provides an overview of Tregs biology, including their functions, suppressive mechanisms, phenotypic markers, as well as their involvement in disease settings. Furthermore, we discuss the therapeutic potential of different Treg subpopulations and their translational applications in the treatment of autoimmune diseases.

Keywords:  Autoimmune diseases; Clinical trials; FoxP3; Rapamycin; Regulatory T cell (Treg); Treg therapy

DOI:  https://doi.org/10.1016/j.intimp.2025.114624
STAR Protoc. 2025 Apr 05. pii: S2666-1667(25)00148-0. [Epub ahead of print]6(2): 103742

Protocol to profile tumor and microenvironment from ovarian cancer patient samples and evaluate cell-based therapy using in vitro killing assays.

Yan-Ruide Li, Christopher J Ochoa, Zibai Lyu, Yichen Zhu, Yuning Chen, Gabriella DiBernardo, Lauryn Ruegg, Sanaz Memarzadeh, Lili Yang.

  Ovarian cancer (OC) presents significant challenges due to late diagnosis and high recurrence rates, necessitating a deeper understanding of the molecular and cellular characteristics of OC and the exploration of novel therapeutic approaches. Here, we provide a protocol to characterize primary OC patient samples, including the tumor and the tumor microenvironment (TME), using flow cytometry. Additionally, we detail the design and evaluation of various cell-based immunotherapies aimed at targeting primary OC tumor and the TME through in vitro killing assays. For complete details on the use and execution of this protocol, please refer to Li et al.1.

Keywords:  Cancer; Cell-based Assays; Flow Cytometry; Immunology

DOI:  https://doi.org/10.1016/j.xpro.2025.103742
Pathol Res Pract. 2025 Mar 31. pii: S0344-0338(25)00114-1. [Epub ahead of print]269 155922

The role of the Androgen Receptor (AR) in endometrial cancer aggressiveness: Correlation with other prognostic markers and therapeutic implications. A retrospective observational study.

Michele Paudice, Marco Greppi, Luca Valle, Nataniele Piol, Fabio Barra, Serafina Mammoliti, Simone Ferrero, Emanuela Marcenaro, Valerio Gaetano Vellone.

  Endometrial carcinoma (EC) is the most common gynecological malignancy, with increasing incidence linked to rising risk factors. This retrospective observational study investigates the role of the Androgen Receptor (AR) in EC aggressiveness, its correlation with other prognostic markers, and its potential therapeutic implications. A total of 143 cases of EC treated with hysterectomy were analyzed for AR expression and its association with clinicopathological and molecular markers, including estrogen receptor (ER), progesterone receptor (PR), Ki-67, p53, β-catenin, E-cadherin, Bcl-2, Cyclin D1, and mismatch repair (MMR) status. AR expression was significantly higher in low-grade endometrioid carcinoma (LGEC) compared to high-grade endometrioid carcinoma (HGEC) and other high-risk histologies (p = 0.015), suggesting a role in less aggressive tumor phenotypes. AR strongly correlated with ER and PR (p < 0.0001), indicating shared regulatory pathways. A borderline association with tumor-infiltrating lymphocytes (TILs) suggests a potential role in immune response. However, AR expression did not significantly correlate with markers of proliferation (Ki-67) or tumor suppression (p53), nor with β-catenin, E-cadherin, Bcl-2, Cyclin D1, or MMR status. These findings support AR as a prognostic marker in hormone-responsive EC subtypes and suggest that AR-targeted therapies could be beneficial, particularly in ER/PR-negative tumors. The study highlights the potential integration of AR status into molecular profiling, aiding in personalized treatment strategies for improved patient outcomes in EC management.

Keywords:  Androgen Receptor (AR); Endometrial Cancer; Hormone Receptors (ER, PR); Molecular Profiling; Prognostic Markers

DOI:  https://doi.org/10.1016/j.prp.2025.155922
PLoS One. 2025 ;20(4): e0321392

Assessment of antigen immunogenicity formulated in minigenes transfected into antigen-presenting cells.

María A Villota-Alava, María A Alfaro-Marenco, Carlos A Clavijo-Ramírez, Manuel A Patarroyo, Carlos A Parra-López.

Tumor cells exhibit deficient antigen presentation to T cells, significantly contributing to immune evasion and tumor genesis. Peptide pulsed Antigen-presenting cells (APCs) are commonly used in cancer immunotherapy to circumvent the defects of tumor cells in processing and presenting antigens to T lymphocytes. However, peptides do not always represent epitopes naturally processed by tumor cells, which might reduce the identification of actual immunogenic antigens. Minigenes encoding concatenated immunogenic tumor epitope sequences offer a promising alternative to select tumor antigens naturally processed and presented to T cells. Hence, using APCs transfected with minigenes might contribute to immunotherapy's effectiveness, avoiding non-naturally processed epitopes as vaccine candidates. This study evaluates APCs transfected with a minigene construct encoding HLA-A0201-restricted immunogenic antigens to stimulate antigen-specific CD8+ T lymphocytes in vitro. Artificial APCs (aAPCs) were also designed by co-transfecting the HEK293 cell line with plasmids encoding co-stimulatory molecules (CD80, CD83, CD137L) to assess CD8+ T cell activation efficiency, intracellular cytokine production, cytotoxic activity, activation and exhaustion marker expression. In this study, we successfully implemented a transfection methodology of HEK293 cells with a minigene encoding viral and tumor HLA-A * 0201 epitopes. These cells, used as aAPCs, allow studying the expansion and the phenotype of antigen-specific CD8+ T cells. However, our results indicate that epitope presentation alone is sufficient to activate CD8+ T cells, suggesting that the presence of co-stimulatory molecules may not be necessary for effective T cell activation. Considering that the use of HEK293 cells as aAPCs has yet to be explored and due to their high transfection efficiency with minigenes, the methodology implemented in this work enables their use to identify naturally processed immunogenic neoantigens. We believe our findings can contribute to selecting and designing personalized vaccines based on tumor neoantigens that are useful for cancer immunotherapy.

DOI: https://doi.org/10.1371/journal.pone.0321392
Mol Cancer. 2025 Apr 09. 24(1): 111

Single-cell and spatial transcriptomic analyses revealing tumor microenvironment remodeling after neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

Xiaolu Cui, Siyuan Liu, He Song, Jingjing Xu, Yanbin Sun.

  Non-small cell lung cancer (NSCLC) represents the most common pathological type of lung cancer, and the combination of neoadjuvant immunotherapy with chemotherapy has emerged as the first-line treatment for NSCLC. Nevertheless, the efficacy of this therapeutic approach remains variable. The present study aims to examine the impact of chemoimmunotherapy in NSCLC patients, with a view to identifying key molecules, critical cell subpopulations, communication patterns and spatial distributions that potentially correlate with therapeutic sensitivity. A total of 16 lung cancer tissue samples were collected from a cohort of 12 NSCLC patients and subjected to single-cell RNA and spatial transcriptome sequencing. Our data demonstrated that the distribution of CD4 + Treg T cells and mCAFs indicated an immunosuppressive tumor microenvironment, while the accumulation of CD4 + Th17 T cells and iCAFs could act as a positive marker for the sensitivity to chemoimmunotherapy. Furthermore, a significant high level of SELENOP-macrophages was observed in tissues from positive responders, and a strong co-localization between SELENOP-macrophages and antigen-presenting cancer associated fibroblasts (CAFs) in the tumor boundaries was identified, indicating the cooperative roles of these two cell types in response to combined therapy. Moreover, SELENOP-macrophages were observed to be accumulated in tertiary lymphoid structures, which further suggested its critical role in recruiting lymphocytes. Furthermore, analysis of cell-cell communication, based on spatial transcriptomics, suggests that the interactions between SELENOP-macrophages, apCAFs, CD4 + and CD8 + T cells were significantly enhanced in responders. In addition, SELENOP-macrophages recruited CD4 + Naïve, Helper and CD8 + Naïve T cells through pathways such as the cholesterol, interleukin, chemokine and HLA when responding to combined therapy. The present study further unveils the dynamic spatial and transcriptional changes in the tumor microenvironment of non-small cell lung cancer in response to combination therapy.

Keywords:  Neoadjuvant chemoimmunotherapy; Non-small cell lung cancer; Single-cell RNA sequencing; Spatial transcriptome; Tertiary lymphoid structures

DOI:  https://doi.org/10.1186/s12943-025-02287-w
Vet Immunol Immunopathol. 2025 Mar 27. pii: S0165-2427(25)00043-1. [Epub ahead of print]283 110923

Evaluation of clinical and immunological responses to recombinant canine interleukin-15 therapy in dogs with cancer: A pilot study.

Y J Lim, M S Lim, J J Lee, H Bae, Y J Baek, G S Kim, Y An, S K Kim, D Yu.

  Interleukin-15 (IL-15) is a pleiotropic cytokine that plays a pivotal role in innate and adaptive immunity. Therefore, it is a promising therapeutic agent for cancer treatment. Despite growing interest in the use of IL-15 as an immunotherapeutic agent, there have been very few reports on its immunological and clinical effects in canine cancers. In this study, we generated recombinant canine IL-15 (rcIL-15) and evaluated its clinical and immunomodulatory effects in combination with metronomic cyclophosphamide in 15 canines with various tumor types. The treatment outcomes were assessed in a prospective clinical trial. Low-dose cyclophosphamide (12.5 mg/m2, PO, SID) was continuously administered for 8 weeks. Starting on day 14, after administering cyclophosphamide, rcIL-15 (20 μg/kg daily) was injected intravenously for 8 days. The disease control rate for combination therapy was 66.6 %, with the most notable partial response accounting for 33.3 % of hematological malignancies. The adverse events were minimal and primarily of grade 1 severity. Moreover, rcIL-15 administration led to significant elevations in anticancer lymphocyte subsets, such as natural killer and cytotoxic T cells, along with increased Ki-67 expression, indicating cellular proliferation. These changes were correlated with improved clinical outcomes. Our findings underscore the therapeutic potential and safety of combining rcIL-15 and metronomic cyclophosphamide for the treatment of various canine cancers.

Keywords:  Canine; Immunotherapy; Interleukin-15; Natural killer cells; Patients with cancer

DOI:  https://doi.org/10.1016/j.vetimm.2025.110923
Front Immunol. 2025 ;16 1524120

A tumor-infiltrating B lymphocytes -related index based on machine-learning predicts prognosis and immunotherapy response in lung adenocarcinoma.

Jiale Fang, Siyuan Yu, Wei Wang, Cheng Liu, Xiaojia Lv, Jiaqi Jin, Xiaomin Han, Fang Zhou, Yukun Wang.

   Introduction: Tumor-infiltrating B lymphocytes (TILBs) play a pivotal role in shaping the immune microenvironment of tumors (TIME) and in the progression of lung adenocarcinoma (LUAD). However, there remains a scarcity of research that has thoroughly and systematically delineated the characteristics of TILBs in LUAD.
Method: The research employed single-cell RNA sequencing from the GSE117570 dataset to identify markers linked to TILBs. A comprehensive machine learning approach, utilizing ten distinct algorithms, facilitated the creation of a TILB-related index (BRI) across the TCGA, GSE31210, and GSE72094 datasets. We used multiple algorithms to evaluate the relationships between BRI and TIME, as well as immune therapy-related biomarkers. Additionally, we assessed the role of BRI in predicting immune therapy response in two datasets, GSE91061 and GSE126044.
Result: BRI functioned as an independent risk determinant in LUAD, demonstrating a robust and reliable capacity to predict overall survival rates. We observed significant differences in the scores of B cells, M2 macrophages, NK cells, and regulatory T cells between the high and low BRI score groups. Notably, BRI was found to inversely correlate with cytotoxic CD8+ T-cell infiltration (r = -0.43, p < 0.001) and positively correlate with regulatory T cells (r = 0.31, p = 0.008). We also found that patients with lower BRI were more likely to respond to immunotherapy and were associated with reduced IC50 values for standard chemotherapy and targeted therapy drugs, in contrast to higher BRI. Additionally, the BRI-based survival prediction nomogram demonstrated significant promise for clinical application in predicting the 1-, 3-, and 5-year overall survival rates among LUAD patients.
Discussion: Our study developed a BRI model using ten different algorithms and 101 algorithm combinations. The BRI could be a valuable tool for risk stratification, prognosis, and selection of treatment approaches.

Keywords:  B-cell; TCGA; immunotherapy; lung cancer; machine learning; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1524120
J Cancer Res Clin Oncol. 2025 Apr 09. 151(4): 135

Revealing tumor microenvironment communication through m6A single-cell analysis and elucidating immunotherapeutic potentials for cutaneous melanoma (CM).

Lun Liu, Maxwell Andriano Kishengere, Xueming Xu, Zhanghui Yue.

   BACKGROUND: The methylation of N6-methyladenosine (m6A) RNA plays a crucial role in the genetic regulation of various cancers. While m6A modifications have been extensively studied in the tumor microenvironment (TME) of several malignancies, their role in cutaneous melanoma (CM) remains unexplored.
METHODS: Using Non-negative matrix factorization (NMF) analysis on single-cell RNA-seq data (GSE215121) from three CM samples obtained from public databases, 26 m6A RNA methylation regulators were utilized to determine TME subclusters, their expression, and function.
RESULTS: Six distinct TME cell types were identified and NMF clustering further revealed unique m6A-based subpopulations of cancer-associated fibroblasts and T cells. The prognostic model demonstrated strong predictive capabilities, particularly for fibroblast and T cell m6A clusters, and highlighted COL3A1 as a critical regulator of melanoma-fibroblast interactions.
CONCLUSION: Highlighting the COL3A1 gene as a critical link and potential therapeutic target in melanoma could offer new avenues for targeted therapies and improve prognostic assessments in cutaneous melanoma.

Keywords:  Cancer-associated fibroblasts; Cell–cell communication; Collagen type III alpha 1 (COL3A1); Cutaneous melanoma; Tumor microenvironment; m6A

DOI:  https://doi.org/10.1007/s00432-025-06176-z
Cell Rep. 2025 Apr 10. pii: S2211-1247(25)00337-7. [Epub ahead of print]44(4): 115566

Pre-existing intratumoral stem-like CD8+ T cells drive radiotherapy-induced tumor immunity.

Hakan Köksal, Michael Herbst, Paulo Perreira, Marc Nater, Nicola Regli, Cheïma Boudjeniba, Nese Erdem Borgoni, Virginia Cecconi, Maries van den Broek.

  CD8+ T cells are crucial for both spontaneous and therapy-induced restriction of tumor progression. Although many patients with cancer undergo radiotherapy, the precise effect of this genotoxic treatment on tumor-associated CD8+ T cells is insufficiently understood. Here, we investigated the influence of radiotherapy on intratumoral CD8+ T cells. We found that, although these CD8+ T cells initially decline following radiotherapy, they subsequently expand and are both essential and sufficient for early tumor control. In response to radiotherapy, stem-like CD8+ T cells proliferate and differentiate into effector CD8+ T cells, making them key drivers of tumor immunity. Our findings underscore the pivotal role of intratumoral stem-like CD8+ T cells in mediating radiotherapy-induced anti-tumor immunity and provide deeper insights into the dynamic behavior of CD8+ T cells during tumor control after radiotherapy.

Keywords:  CP: Cancer; CP: Immunology; TCF-1; cancer; radiotherapy; stem-like CD8(+) T cells

DOI:  https://doi.org/10.1016/j.celrep.2025.115566
bioRxiv. 2025 Mar 29. pii: 2025.03.25.645281. [Epub ahead of print]

The spontaneous neoantigen-specific CD4 + T cell response to a growing tumor is functionally and phenotypically diverse.

Ryan Q Griswold, Spencer E Brightman, Karla Soria Zavala, Manuel Azaid Ordaz-Arias, Navid Djassemi, Rukman R Thota, Martin S Naradikian, Hannah Dose, Suzie Alarcon, Vijayanand Pandurangan, Bjoern Peters, Aaron M Miller, Ezra E W Cohen, Stephen P Schoenberger.

CD4 + T cells play critical roles in the positive and negative regulation of cellular immunity through the many functional subsets they comprise. The progressive growth of immunogenic tumors which nonetheless generate mutation-specific T cells suggests that effective immune control may be avoided or suppressed at the level of the neoantigen-specific CD4 + T cell response. We used a tetramer specific for a validated neoantigen, CTLC H129>Q /I-E k , to characterize the ontogeny of natural CD4 + T cell responses to an aggressive and poorly immunogenic Major Histocompatibility Complex Class II (MHCII)-deficient tumor, SCC VII, during progressive growth or following therapeutic peptide vaccination. We find that the natural CD4 + T cell response to a growing tumor is phenotypically and functionally diverse, with distinct subsets including type 1 helper (T h 1), T follicular helper (T fh )-like, and regulatory T cell (T reg ) lineages appearing as early as 9 days after tumor implantation. Therapeutic vaccination using the CLTC H129>Q peptide in adjuvant plus α-PD-1 sharply reduces the frequency of CLTC H129>Q -specific T reg frequency in both tumor and tumor-draining lymph node (tdLN). Single cell transcriptomic analysis of CLTC-specific CD4 + T cells recapitulated and extended the diversity of the response, with TCRs of varying affinity found within each functional subset. The TCR affinity differences did not strictly correlate with function, however, as even the lowest affinity TCRs isolated from T reg can mediate therapeutic efficacy against established tumors in the setting of adoptive cellular therapy (ACT). These findings offer unprecedented insight into the functional diversity of a natural neoantigen-specific CD4 + T cell response and show how immunotherapeutic intervention influences the phenotype, magnitude, and efficacy of the anti-tumor immune response.
What is already known on this topic: Little is known about the ontogeny, architecture, development of the CD4 + NeoAg-specific repertoire induced by progressively-growing tumor. This study was performed to address this topic and contribute new information to aid in its understanding.
What this study adds: This study reveals that the NeoAg-specific CD4 + T cell response to a growing tumor is phenotypically and functionally diverse, featuring a range of functional T cells subsets including T H 1, T FH , and T reg expressing a range of functional TCR avidities, and demonstrates how an immunotherapeutic NeoAg vaccine can alter their relative composition within the tumor and tumor-draining lymph node.
How this study might affect research practice or policy: This study offers new insights into the diversity of NeoAg-specific CD4 + T cells and their response to a tumor in the presence or absence of immunotherapeutic intervention. This information could lead to new approaches to immune monitoring in the clinical setting of checkpoint blockade immunotherapy and cancer vaccines. Furthermore, we show that T reg can be a potent source of TCRs that can mediate therapeutic benefit in the setting of adoptive cell therapy (ACT).

DOI: https://doi.org/10.1101/2025.03.25.645281
Int J Urol. 2025 Apr 11.

Tertiary Lymphoid Structures Correlate With Better Prognosis in Patients With Retroperitoneal Sarcoma: A Retrospective Study.

Toshiki Kijima, Atsuko Takada-Owada, Hidetoshi Kokubun, Toshitaka Uematsu, Kohei Takei, Hironori Betsunoh, Masahiro Yashi, Kazuyuki Ishida, Takao Kamai.

   OBJECTIVE: To evaluate the prognostic impact of intratumoral tertiary lymphoid structures (TLSs) in patients with retroperitoneal sarcoma undergoing primary curative surgery, focusing on their relationship with immune microenvironment components and survival outcomes.
METHODS: We conducted a retrospective analysis of 29 patients who underwent surgical resection for retroperitoneal sarcoma at Dokkyo Medical University Hospital from 2007 to 2021. TLSs and tumor-infiltrating lymphocytes were assessed in surgical specimens using immunohistochemical staining to identify CD20-positive B, CD3-positive T, and CD8-positive T cells. Disease-specific survival was analyzed via Kaplan-Meier and Cox proportional hazards models, identifying key prognostic factors.
RESULTS: TLSs were identified in 59% of patients, with the highest density in dedifferentiated liposarcoma (DDLPS). TLS-positive patients showed significantly improved survival compared with TLS-negative patients, with the greatest survival observed in those with ≥ 10 TLSs per 100 mm2. TLS density was also associated with increased CD8-positive T-cell infiltration, indicating a potentially enhanced immune response. In the subset of DDLPS cases, TLS positivity correlated with prolonged survival, underscoring its prognostic value.
CONCLUSIONS: Intratumoral TLSs are associated with improved survival in retroperitoneal sarcoma, especially DDLPS. These findings highlight the need for further studies on the role of TLS maturity and immune microenvironment dynamics in shaping prognosis and treatment outcomes in retroperitoneal sarcoma.

Keywords:  prognosis; retroperitoneal sarcoma; retrospective study; tertiary lymphoid structures

DOI:  https://doi.org/10.1111/iju.70069