bims-tuinly 2025-01-05 papers

Transl Oncol. 2024 Dec 29. pii: S1936-5233(24)00391-7. [Epub ahead of print]52 102265

Prognostic implications of immune classification based on PD-L1 expression and tumor-infiltrating lymphocytes in endocervical adenocarcinoma.

Li-Jun Wei, Zi-Yun Wu, Li-Yan Wu, Ying-Wen Wu, Hao-Yu Liang, Rong-Zhen Luo, Li-Li Liu.

BACKGROUND: Endocervical adenocarcinoma (ECA) comprises a heterogeneous group of diseases whose incidence has increased significantly in recent decades. ECA can be histologically classified into human papillomavirus-associated (HPVA) and non-HPVA (NHPVA) types. Given the variability in pathological features and clinical behavior between the subtypes, evaluating their respective immune microenvironments is essential. They can be categorized into distinct tumor microenvironment immune types (TMIT).
METHODS: A total of 540 surgically resected ECA samples were classified into HPVA and NHPVA subgroups. Tumor-infiltrating immune markers were assessed using immunohistochemistry. We categorized ECA into four TMIT based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs) expression, and analyzed their prognostic significance.
RESULTS: PD-L1 positivity was observed in 319 out of 464 (68.8%) HPVA and 55 out of 76 (72.4%) NHPVA. Across the entire cohort, high CD8+ TILs expression was significantly associated with improved disease-free survival (DFS, p=0.018) and overall survival (OS, p=0.031). A total of 177 samples (32.8%) were classified as TMIT I (high PD-L1 and high CD8+ TILs), exhibiting markedly denser immune cell infiltration compared to the other TMIT groups. In NHPVA subgroup, TMIT was significantly associated with both DFS (p=0.005) and OS (p=0.003). Multivariate analysis identified TMIT as an independent prognostic factor for DFS in the NHPVA group, with TMIT I indicating a more favorable prognosis (p=0.042).
CONCLUSIONS: TMIT I group within the NHPVA population is most likely to benefit from PD-L1/PD-1 blockade immunotherapies. The immune classification of ECA demonstrates significant prognostic value, suggesting its potential utility in guiding clinical stratification and therapeutic decision-making.

Keywords: Endocervical adenocarcinoma; PD-L1; Prognosis; Tumor-infiltrating lymphocytes

DOI: https://doi.org/10.1016/j.tranon.2024.102265

Pathologica. 2024 Dec;116(6): 390-403

A Digital Workflow for Automated Assessment of Tumor-Infiltrating Lymphocytes in Oral Squamous Cell Carcinoma Using QuPath and a StarDist-Based Model.

Angela Crispino, Silvia Varricchio, Gennaro Ilardi, Daniela Russo, Rosa Maria Di Crescenzo, Stefania Staibano, Francesco Merolla.

The search for reliable prognostic markers in oral squamous cell carcinoma (OSCC) remains a critical need. Tumor-infiltrating lymphocytes (TILs), particularly T lymphocytes, play a pivotal role in the immune response against tumors and are strongly correlated with favorable prognoses. Computational pathology has proven highly effective for histopathological image analysis, automating tasks such as cell detection, classification, and segmentation.
In the present study, we developed a StarDist-based model to automatically detect T lymphocytes in hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) of OSCC, bypassing the need for traditional immunohistochemistry (IHC). Using QuPath, we generated training datasets from annotated slides, employing IHC as the ground truth. Our model was validated on Cancer Genome Atlas-derived OSCC images, and survival analyses demonstrated that higher TIL densities correlated with improved patient outcomes.
This work introduces an efficient, AI-powered workflow for automated immune profiling in OSCC, offering a reproducible and scalable approach for diagnostic and prognostic applications.

Keywords: Computational Pathology; Digital Pathology; IA; OSCC; QuPath; StarDist; T lymphocyte cells; deep learning

DOI: https://doi.org/10.32074/1591-951X-1069

Front Immunol. 2024 ;15 1504220

High density of TCF1+ stem-like tumor-infiltrating lymphocytes is associated with favorable disease-specific survival in NSCLC.

Dagny Førde, Thomas Kilvær, Mona Irene Pedersen, Egil S Blix, Ilona Urbarova, Erna-Elise Paulsen, Mehrdad Rakaee, Lill-Tove Rasmussen Busund, Tom Donnem, Sigve Andersen.

Introduction: Tumor-infiltrating lymphocytes are both prognostic and predictive biomarkers for immunotherapy response. However, less is known about the survival benefits oftheir subpopulations.
Methods: Using machine learning models, we assessed the clinical association of the CD8+, PD1+, TCF1+ cel l subset by multiplex immunohistochemistry using tissue microarrays in 553 non-small cell lung cancer (NSCLC) patients and its correlation with other immune cell biomarkers.
Results: We observed positive correlations between TCF1 and CD20 (r=0.37), CD3 (r=0.45)and CD4 (r=0.33). Notably, triple positive (CD8+PD1+TCF1+) were rare, only observed in 29 of 553 patients (5%). Our analysis revealed that cells coexpressing TCF1 with either CD8+ or PD1+ were independent prognostic markers of disease-specific survival in multivariable analysis (HR=0.728, p=0.029 for CD8+TCF1+, and HR=0.612, p=0.002 for PD1+TCF1+). To pilot the subtype of abundant CD8-TCF1+ cells, we explored an immune cell infiltrated whole slideimage and found the majority to be CD4+.
Discussion: Overall, these findings suggest that assessment of CD8+, PD1+, TCF1+ could serve as a potential prognostic biomarker in NSCLC.

Keywords: CD8; NSCLC; PD1; TCF1; digital pathology; machine learning

DOI: https://doi.org/10.3389/fimmu.2024.1504220

Cancer Immunol Immunother. 2025 Jan 03. 74(2): 55

CCR5 and IL-12 co-expression in CAR T cells improves antitumor efficacy by reprogramming tumor microenvironment in solid tumors.

Yonggui Tian, Liubo Zhang, Yu Ping, Zhen Zhang, Chang Yao, Chunyi Shen, Feng Li, Chunli Wen, Yi Zhang.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors faces significant challenges, including inadequate infiltration, limited proliferation, diminished effector function of CAR T cells, and an immunosuppressive tumor microenvironment (TME). In this study, we utilized The Cancer Genome Atlas database to identify key chemokines (CCL4, CCL5, and CCR5) associated with T cell infiltration across various solid tumor types. The CCL4/CCL5-CCR5 axis emerged as significantly correlated with the presence of T cells within tumors, and enhancing the expression of CCR5 in CAR T cells bolstered their migratory capacity. Furthermore, single-cell immunoprofiling of tumor tissues revealed that macrophages within the TME primarily interact with CD8+ T cells, impeding their tumor response. However, CAR T cells engineered to secrete Interleukin (IL)-12 can counteract macrophage-mediated immunosuppression and augment T cell functionality. To address these obstacles, we employed esophageal carcinoma as a model to develop mesothelin-targeted CAR T cells co-expressing CCR5 and IL-12 (CARTmeso-5-12), subsequently assessing their antitumor capabilities in vitro and in vivo. The CARTmeso-5-12 cells demonstrated enhanced tumor infiltration due to overexpression of CCR5, and IL-12 secretion further amplified CAR T cell efficacy by attenuating the suppressive influence of tumor-infiltrating macrophages, thus improving tumor eradication.

Keywords: CAR T cells; CCR5; IL-12; Tumor Mircoenvironment

DOI: https://doi.org/10.1007/s00262-024-03909-w

Front Immunol. 2024 ;15 1501365

In vivo programmed myeloid cells expressing novel chimeric antigen receptors show potent anti-tumor activity in preclinical solid tumor models.

Shannon Argueta, Yuxiao Wang, Hongyun Zhao, Neha Diwanji, Michael Gorgievski, Edward Cochran, Ewa Grudzien-Nogalska, Josephine D'Alessandro, Bruce McCreedy, Thomas Prod'homme, Robert Hofmeister, Jian Ding, Daniel Getts.

Introduction: The approval of chimeric antigen receptor (CAR) T cell therapies for the treatment of B cell malignancies has fueled the development of numerous ex vivo cell therapies. However, these cell therapies are complex and costly, and unlike in hematological malignancies, outcomes with most T cell therapies in solid tumors have been disappointing. Here, we present a novel approach to directly program myeloid cells in vivo by administering novel TROP2 CAR mRNA encapsulated in lipid nanoparticles (LNPs).
Methods: The CAR comprises a TROP2 specific single-chain variable fragment (scFv) fused to a truncated CD89 which requires association with the FcRγ signal adapter to trigger myeloid-specific cell activation. The mRNA encoding the TROP2 CAR was encapsulated in LNPs. Co-immunoprecipitation, flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to measure CAR expression and functional activity in vitro. Anti-tumor efficacy of the TROP2 CAR mRNA/LNP was evaluated after intravenous administration in various murine tumor models.
Results: In vitro, transient expression of the TROP2 CAR on monocytes triggers antigen-dependent cytotoxicity and cytokine release. In tumor bearing mice and cynomolgus monkeys, the TROP2 CAR mRNA/LNP are primarily expressed by myeloid cells. In a mouse xenograft model, intravenous administration of TROP2 CAR mRNA/LNP results in tumor growth inhibition and in a B16/F10-OVA immunocompetent melanoma mouse model, anti-tumor efficacy of a gp75-specific CAR correlates with increased number of activated T cells, activation of dendritic cells and a humoral response against B16/F10-OVA melanoma tumors.
Discussions: These findings demonstrate that myeloid cells can be directly engineered in vivo to kill tumor cells and orchestrate an adaptive immune response and guide clinical studies for the treatment of solid tumors.

Keywords: RNA therapeutics; cancer therapy; cell therapy; lipid nanoparticles; myeloid cells

DOI: https://doi.org/10.3389/fimmu.2024.1501365