bims-tuinly 2025-09-14 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–09–14
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

The Critical Role of Homing in TIL Therapy Success: From Biology to Clinical Application.
Immune activation following PD-L1 inhibitor plus chemoradiotherapy in locally advanced rectal cancer: a retrospective, single-arm study.
Do AR and TILs have any association with the efficacy of neoadjuvant treatment for HER2-positive breast cancer?
Live biotherapeutic enterococcus lactis MNC-168 promotes the efficacy of immune checkpoint blockade in cancer therapy by activating STING pathway via bacterial membrane vesicles.
Neighborhood clustering analysis to define epithelial-stromal interface for tumor infiltrating lymphocyte evaluation.
Preclinical evaluation of folate receptor-alpha chimeric antigen receptor T cells (FOLR1-CART) exhibit highly efficient anti-tumor activity against osteosarcoma.
Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and Akkermansia muciniphila to regulate gut microbial metabolite 5-HIAA.
Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
GD2-Specific CAR T Cells Demonstrate Potent and Targeted Anti-Tumor Efficacy Against Melanoma In Vitro and In Vivo.
Bispecific antibodies cross-link and redirect CD8+ T cells to kill cytomegalovirus-infected cells.

Crit Rev Oncol Hematol. 2025 Sep 09. pii: S1040-8428(25)00318-X. [Epub ahead of print] 104930

The Critical Role of Homing in TIL Therapy Success: From Biology to Clinical Application.

Yousef Mohammadi, Hossein Khorramdelazad, Narjes Soleimanifar, Mohsen Badalzadeh, Mohammad Hossein Nicknam, Gholam Ali Kardar.

  Tumor-infiltrating lymphocyte (TIL) therapy has shown promising results in the treatment of advanced malignancies by harnessing autologous T cells expanded ex-vivo for reinfusion. Despite its recent FDA approval and durable clinical responses in melanoma patients, the success and applicability of TIL therapy across multiple tumor types are still limited by a key obstacle: the poor homing and infiltration of transfused TILs into the tumor microenvironment (TME). In this review, we outline the various barriers to TIL trafficking, including tumor-intrinsic mechanisms such as chemokine dysregulation, oncogenic signaling, and metabolic reprogramming, as well as tumor-extrinsic factors, including stromal remodeling, abnormal vasculature, and immunosuppressive cell populations. We introduce a conceptual framework for categorizing tumors based on immune exclusion phenotypes and discuss how these classifications influence TIL infiltration and clinical outcomes. Furthermore, we highlight strategies to overcome these barriers, including chemokine receptor engineering, modulation of the TME, and combinatorial approaches. By analyzing the complex interaction between TILs and the TME, this review provides a roadmap to enhance the precision and effectiveness of TIL-based immunotherapies across a broader range of solid tumors.

Keywords:  Adoptive Cell Transfer; Cell Engineering; Chemokine; Homing; Immune Evasion; TIL Therapy

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104930
Front Immunol. 2025 ;16 1619043

Immune activation following PD-L1 inhibitor plus chemoradiotherapy in locally advanced rectal cancer: a retrospective, single-arm study.

Shaoqing Fan, Zeming Zhao, Qingyu Meng, Haiqian Wang, Bin Yu, Wenbo Niu.

   Background: Locally advanced rectal cancer (LARC) is challenging due to high recurrence rates and poor responses to neoadjuvant chemoradiotherapy (nCRT). Combining nCRT with immunotherapy may enhance antitumor immunity by modifying the tumor microenvironment (TME). This study evaluates the efficacy of nCRT with PD-L1 inhibitor envafolimab in LARC and explores its impact on TME.
Methods: In this retrospective, single-arm design study, 36 LARC patients (T3+/N1-2/M0) received long-course radiotherapy (50.4 Gy/28 fractions) with capecitabine, followed by two cycles of XELOX chemotherapy and envafolimab. Pathological complete response (pCR) and tumor regression grade (TRG) were assessed post-surgery. Immunohistochemical analysis quantified CD4+, CD8+ T cells, and CD56+ NK cell infiltration in paired pre- and post-treatment tumor tissues.
Results: The pCR rate was 47.2% (17/36), with 94.4% and 86.1% achieving T- and N-downstaging. Post-treatment tumor-infiltrating lymphocytes (TILs) increased, with CD8+ T cells showing the most significant infiltration (Grade 3: +6 cases, P<0.05). Higher baseline TIL density correlated with better TRG outcomes (TRG0-2: 94.4% vs. TRG3: 5.6%).
Conclusion: nCRT combined with envafolimab enhances immune cell infiltration, particularly CD8+ T cells, achieving high pCR rates in LARC. This approach enhances cytotoxic immunity while addressing immunosuppressive barriers. Further studies should explore strategies to overcome TME resistance.

Keywords:  PD-L1 inhibitor; locally advanced rectal cancer; neoadjuvant chemoradiotherapy; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2025.1619043
Medicine (Baltimore). 2025 Sep 05. 104(36): e44364

Do AR and TILs have any association with the efficacy of neoadjuvant treatment for HER2-positive breast cancer?

Xi-Hao Ni, Wei-Tao Wang, Ran An, Sen Gao, Jun Zhang, Chang-Liang Wang.

  The presence of androgen receptor (AR) as a marker can be detected in all breast cancer subtypes, and it may provide information on treatment response and prognosis. This study aimed to examine the correlation between AR expression and treatment response in patients diagnosed with human epidermal growth factor receptor 2 (HER2) positive breast cancer who were undergoing neoadjuvant therapy (NAT). The evaluation included breast cancer patients who received NAT and underwent surgery at Weifang People's Hospital's Department of Breast Surgery between October 2019 and October 2022. We examined and compared the clinical and pathological factors between patients who achieved a pathological complete response (pCR) and those who did not. Statistical methods: The statistical analysis was conducted utilizing SPSS 17.0 software. Univariate and multivariable analyses were employed to establish the association between each variable and pCR. Independent variables included in the multivariable analyses were those factors deemed significant (P < .05) in the chi-square test of univariate analysis. Variables with a P-value < 0.05 were regarded as being independent influencing factors. Survival curves were generated using the Kaplan-Meier method. A total of 63 patients were included, all of whom had received NAT, with an overall pCR rate of 31.7%. pCR was positively correlated with AR positivity (OR = 0.105 [95% CI = 0.012~0.939], P = .044) and high density of tumor-infiltrating lymphocytes (TILs) (OR = 0.134 [95% CI = 0.031~0.586], P = .008). Receiver operating characteristic (ROC) curves had been plotted to assess the predictive value of AR expression and the density of TILs for pCR, with areas under the curves being 0.661 (95% CI = 0.573-0.749, P = .044) and 0.716 (95% CI = 0.606-0.825, P = .008), respectively. Potential biomarkers for pCR in HER2-positive breast cancer patients receiving NAT may include the expressions of AR and TILs.

Keywords:  HER2-positive breast cancer; androgen receptor; neoadjuvant therapy; pathological complete response; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1097/MD.0000000000044364
Gut Microbes. 2025 Dec;17(1): 2557978

Live biotherapeutic enterococcus lactis MNC-168 promotes the efficacy of immune checkpoint blockade in cancer therapy by activating STING pathway via bacterial membrane vesicles.

Yibo Xian, Zhipeng Chen, Zhou Lan, Chenchen Zhang, Hao Sun, Zhenzhen Liu, Ping Kong, Yajun Liang, Yingying Zhao, Si-Yang Maggie Liu, Yiqi Zhou, Linchuan Gan, Baoxia Li, Xue Su, Baojia Huang, Chen Xiao, Ruijuan Zhu, Guozhen Zhao, Canshan Lao, Chuan-Sheng Lin, Dongya Zhang, Xianzhi Jiang.

  The gut microbiome has the potential to influence tumor development and affect the efficacy of cancer therapeutics, particularly immunotherapy. However, the specific species and strains rather than all microbes that promote antitumor immunity by modulating the function of systemic immunity or tumor-infiltrating lymphocytes (TILs) in tumor environments remain to be elucidated. In this study, we analyzed the microbiome composition of responders and non-responders to PD-1 blockade therapy from a clinical cohort and found that Enterococcus spp. were abundant in the responders. Through in vitro screening, we identified Enterococcus lactis MNC-168, a commensal bacterium isolated from a healthy individual, which significantly inhibited tumor growth and enhanced the efficacy of anti-PD-1 treatment by promoting antitumor immunity. Mechanistically, MNC-168 activates innate immunity through a STING-IFN-I (stimulator of interferon genes-type I interferons) dependent pathway by releasing bacterial membrane vesicles (MVs), and targeting tumor tissue, thereby augmenting the antitumor immune response. Furthermore, we have confirmed the safety profile of MNC-168 and its enhancing effect on Anti-PD-1 activity across multiple preclinical models, as well as its potential clinical relevance to Anti-PD-1 therapy. These findings suggest that MNC-168 could represent a promising strategy for cancer therapy and has the potential to improve the efficacy of current immunotherapies.

Keywords:  Enterococcus lactis; MNC-168; STING; bacterial membrane vesicles; immune system; immunotherapy

DOI:  https://doi.org/10.1080/19490976.2025.2557978
J Pathol Inform. 2025 Nov;19 100465

Neighborhood clustering analysis to define epithelial-stromal interface for tumor infiltrating lymphocyte evaluation.

Tony Yeung, Yi Zhang, Qianghua Zhou, Richard Burack.

  Evaluation of tumor infiltrating lymphocytes as recommended by current guidelines is largely based on stromal regions within the tumor. In the context of epithelial malignancies, the epithelial region and the epithelial-stromal interface are not assessed, because of technical difficulties in manually discerning lymphocytes when admixed with epithelial tumor cells. The inability to quantify immune cells in epithelial-associated areas may negatively impact evaluation of patient response to immune checkpoint therapies. Innovative spatial analysis techniques have emerged that can directly address challenges associated with quantification of lymphocytes in specialized regions like the interface. In this study, we apply supervised neighborhood clustering analysis (via an open-source application CytoMAP) to assess the spatial distribution of CD8+ T cells, CD8+ TIM3+ (T cell immunoglobulin and mucin-domain containing-3) exhausted T cells, and TIM3+ CD8- macrophages on a gynecological tumor microarray. Neighborhood clustering analysis is adept at objectively mapping the epithelial-stromal interface alongside the epithelial and stromal region of each tumor under a three-compartment model. When tumors are partitioned by the conventional two-compartment model (epithelial and stromal region only), the highest density of total CD8+ T cells is found in the stromal region in a slight majority of tumors. In contrast, the interface region surpasses both the epithelial and stromal region in holding the highest density of CD8+ T cells when this unique region is incorporated into the three-compartment model. Further subset analysis shows higher proportion of CD8+ TIM3+ exhausted T cells within the interface and epithelial region, as compared to CD8+ TIM3- T cells which span from the stroma to the interface. These results highlight the utility of implementing quantitative spatial technique and immune subset analysis in the assessment of tumor infiltrating lymphocytes, and underscore the potential significance of the under-reported tumor epithelial-stromal interface.

Keywords:  CD8; Epithelial–stromal interface; High-grade serous carcinoma; Immune checkpoint blockade therapy; Low-grade endometrial carcinoma; Multiplex immunofluorescence imaging; Neighborhood clustering analysis; Spatial heterogeneity; T cell immunoglobulin and mucin-domain containing-3 (TIM3); Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jpi.2025.100465
Cancer Res Commun. 2025 Sep 08.

Preclinical evaluation of folate receptor-alpha chimeric antigen receptor T cells (FOLR1-CART) exhibit highly efficient anti-tumor activity against osteosarcoma.

Michelle Choe, Danielle Kirkey, Isabel Lira, Grace Hawkins, Melia Blankenfeld, Sarah Menashe, Rhonda Ries, Brianna Wrightson, Christina Root, Cyd N McKay, Jack H Peplinski, Raisa Glabman, Lara E Davis, Sanjay V Malhotra, Richard Gorlick, Elizabeth T Loggers, Soheil Meshinchi.

Metastatic and relapsed osteosarcoma (OS) remains difficult to treat despite advanced surgical techniques, intensified chemotherapy, and targeted therapies. Adoptive immunotherapies such as chimeric antigen receptor (CAR) T cells, are in their nascent stage, but remain a viable therapeutic strategy for patients with aggressive solid tumors such as OS. Folate receptor- (FOLR1) has been functionally implicated in OS pathophysiology, providing rationale as a potential therapeutic target. We recently advanced a FOLR1-specific CAR T cell product (FH FOLR1-CART) into a trial in infant AML (NCT06609928) and now evaluate this CAR construct against OS. We provide comprehensive FOLR1 transcript and protein expression profile in OS patients, cell lines and patient-derived xenografts, substantiating its significance as a therapeutic target. We further evaluate in vitro and in vivo efficacy of FH FOLR1-CART in both standard and patient-derived OS cell lines and xenograft models. FOLR1 transcript is expressed in the overwhelming majority of OS primary patient specimens, in OS cell lines, and patient-derived models. FH FOLR1-CART exhibit robust in vitro activation and potent cytotoxicity against FOLR1-expressing OS cell lines and primary OS patient samples. More importantly, FH FOLR1-CART demonstrates potent anti-tumor activity in both localized and metastatic in vivo cell-derived and patient-derived xenograft models, with complete tumor eradication. These results demonstrate a potential therapeutic option for patients with advanced OS. FH FOLR1 CART is advancing to an early phase trial in relapsed/refractory OS at Fred Hutch Cancer Center and Seattle Children's Hospital.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0086
J Immunother Cancer. 2025 Sep 10. pii: e011831. [Epub ahead of print]13(9):

Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and Akkermansia muciniphila to regulate gut microbial metabolite 5-HIAA.

Shilong Sun, Longhao Wang, Kang Cui, Yuchao Ding, Yujie Wei, Yuanyuan Zheng, Zhibo Shen, Lili Zhu, Yaqi Yang, Pu Yu, Yiqiong Song, Ke Chao, Yixing Zhang, Yahao Ge, Wenxuan Ji, Chunwei Li, Gautam Sethi, Lifeng Li, Jie Zhao.

   BACKGROUND: Improving the efficacy of anti-programmed death 1 (PD-1) monoclonal antibody (mAb) therapy remains a major challenge for cancer immunotherapy in non-small cell lung cancer (NSCLC). Gut microbial metabolites can influence immunotherapy efficacy.
METHODS: ELISA was used to compare the serum 5-hydroxyindoleacetic acid (5-HIAA) level in patients with NSCLC. Humanized mice were constructed to observe the effect of 5-HIAA on immunotherapy. RNA-seq and flow cytometry were used to analyze the effect of 5-HIAA on tumor-infiltrating lymphocytes. The effects of phenelzine (Phe) and Akkermansia muciniphila (AKK) on 5-HIAA synthesis, antitumor immunity and immunotherapy efficacy were analyzed. Finally, the synergistic effect of Phe combined with AKK on anti-PD-1 mAb was observed.
RESULTS: Here we found that 5-HIAA, which is regulated by gut microbiota, has increased concentrations in the serum of non-responders to immunotherapy. Supplementation of 5-HIAA inhibited the efficacy of anti-PD-1 mAb and tumor infiltration of CD8+ T cells. The use of monoamine oxidase inhibitor (MAO-I) Phe inhibited the synthesis of 5-HIAA, then improved the efficacy of anti-PD-1 mAb. In addition, supplementation of AKK can also decrease 5-HIAA in serum. Finally, the combination of Phe and AKK maximally inhibited 5-HIAA synthesis and improved immunotherapy efficacy.
CONCLUSIONS: Our investigations reveal that alterations in gut microbial composition leading to increased 5-HIAA synthesis can negatively impact CD8+ T cell functionality and the success of immunotherapy. The combination of Phe and AKK supplementation holds potential for optimizing immunotherapy efficacy.

Keywords:  Immunotherapy; Lung Cancer

DOI:  https://doi.org/10.1136/jitc-2025-011831
Immunity. 2025 Sep 03. pii: S1074-7613(25)00371-1. [Epub ahead of print]

Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.

Dayana B Rivadeneira, Sanjana Thosar, Kevin Quann, William G Gunn, Victoria G Dean, Bingxian Xie, Angelina Parise, Andrew C McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P Barnes, Marcel P Bruchez, Patricia L Opresko, Greg M Delgoffe.

  The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.

Keywords:  DNA damage; ROS; T cell dysfunction; adoptive cell therapy; mitochondria; telomere; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2025.08.008
Front Biosci (Landmark Ed). 2025 Aug 25. 30(8): 41221

GD2-Specific CAR T Cells Demonstrate Potent and Targeted Anti-Tumor Efficacy Against Melanoma In Vitro and In Vivo.

Julia Philippova, Julia Shevchenko, Alaa Alsalloum, Marina Fisher, Saleh Alrhmoun, Roman Perik-Zavodskii, Olga Perik-Zavodskaia, Julia Lopatnikova, Vasily Kurilin, Marina Volynets, Evgenii Zavjalov, Olga Solovieva, Hiroshi Shiku, Sergey Sennikov.

   BACKGROUND: Disialoganglioside (GD2) is a tumor-associated antigen that is highly expressed in various neuroectodermal cancers, including melanoma. While chimeric antigen receptor (CAR) T-cell immunotherapy has demonstrated remarkable success in treating hematologic neoplasms, the identification of suitable targets remains a major obstacle in translating this approach to solid tumors.
METHODS: Peripheral blood T lymphocytes from six healthy donors were used to generate GD2-specific CAR T cells via retroviral transduction. The resulting GD2.CAR T cells were characterized by NanoString transcriptome profiling, flow cytometry with hierarchical stochastic neighbor embedding (HSNE) dimensionality reduction, and in vitro cytotoxicity assays against GD2+ and GD2- melanoma cell lines. In vivo experiments were also performed using GD2+ xenograft models and a single intratumoral dose of 8 × 106 GD2.CAR T cells.
RESULT: The GD2.CAR T cell population exhibited a predominantly naive phenotype (CD8+CD40L+CD69‒CD107a+4-1BB+FasL+) and effective anti-tumor mechanisms involving the granzyme A/B axis, the Fas/FasL axis, and cytokine release. Transcriptome analysis revealed transduction-related effects on proliferation and a shift towards an effector phenotype during early co-culture with tumor cells, accompanied by upregulation of interferon-gamma (IFN-γ) and cytokine signaling genes. GD2.CAR T cells demonstrated robust cytotoxicity against GD2+ melanoma cells in vitro, while significant in vivo tumor control was observed in xenograft models.
CONCLUSION: GD2.CAR T cells demonstrate potent anti-tumor activity against melanoma in vitro and in vivo, highlighting their therapeutic potential and warranting further clinical investigation.

Keywords:  CAR T cells; cytotoxicity; disialoganglioside; transcriptome profiling; xenograft model

DOI:  https://doi.org/10.31083/FBL41221
Sci Adv. 2025 Sep 12. 11(37): eady2092

Bispecific antibodies cross-link and redirect CD8+ T cells to kill cytomegalovirus-infected cells.

Ayub Ali, Arumugam Balamurugan, Francisco J Ibarrondo, Minh Nguyen, Sara Habibipour, Jaimie M Lim, Christian Hofmann, Hwee L Ng, Otto O Yang.

Adoptive transfer studies of ex vivo-expanded autologous cytomegalovirus (CMV)-specific CD8+ T lymphocytes (CTLs) in immunocompromised hosts demonstrate a central role for viral control, but this therapeutic approach is not generally feasible. We present T cell-redirecting bispecific antibodies (TRBAs) that cross-link CD3ε on CTLs to gH protein on CMV-infected cells, including versions where a single-chain antibody is appended to the carboxyl terminus of the heavy chain of a regular antibody, or where both light and heavy chains have two tandem variable regions in a crossover ordered design. Both versions bind both antigens and mediate the specific clearance of infected cells with the release of interferon-γ when added to CTLs with CMV-infected cells. TRBA-mediated clearance is visualized with physical clustering of CTLs with CMV-infected cells. These results illustrate the mechanism and utility of these TRBAs as potential therapeutic candidates for disseminated CMV infection, with potential advantages compared to two prior CMV-specific TRBAs.

DOI: https://doi.org/10.1126/sciadv.ady2092