bims-tuinly 2025-03-09 papers

Annu Int Conf IEEE Eng Med Biol Soc. 2024 Jul;2024 1-4

Feature Engineering Assessment of Tumor Infiltrating Lymphocytes in Lung Adenocarcinoma.

Giulia Bruschi, Agnese Sbrollini, Federica Pecci, Valeria Cognigni, Francesco Paoloni, Tommaso Galassi, Luca Cantini, Micaela Morettini, Rossana Berardi, Laura Burattini.

Tumor-Infiltrating Lymphocytes (TIL) are emerging as immunotherapy prognostic markers. Currently, TIL are assessed on hematoxylin and eosin (H&E)-stained slides of tumor tissue by pathologists. This approach is time-consuming, and subjected to inter-observer variability. The aim of this study is to propose a machine learning-based algorithm, called Feature Engineering TIL Assessment (FTA), for the automatic TIL assessment by using adenocarcinoma metadata (i.e., anamnestic, clinical and pathological data). The algorithm is an Elastic Net, tuned by Bayesian Optimization and validated by Leave-One-Subject-Out cross validation. Obtained coefficients were used for feature ranking. Results confirms the goodness of performance of FTA, with an overall Mean Absolute Error of 2.1%, Concordance Correlation Coefficient equal to 0.71 and difference in the Bland- Altman plot equal to -0.001. The obtained feature ranking revealed the key role of gender, as confirmed by the clinical literature. In conclusion, FTA is the first image-independent automatic TIL assessment procedure, having the potential to address challenges associated with inter-observer variability and the time-consuming nature of classical procedures.

DOI: https://doi.org/10.1109/EMBC53108.2024.10782758

Ann Diagn Pathol. 2025 Mar 03. pii: S1092-9134(25)00027-9. [Epub ahead of print]76 152462

Development of a digital algorithm for assessing tumor-stroma ratio, tumor budding and tumor infiltrating lymphocytes in vulvar squamous cell carcinomas.

Louise Baandrup, Susanne K Kjær, Óli Jacobsen, Michael Bzorek, Thomas Thiilmark Eriksen, Lise Grupe Larsen, Anne-Marie Kanstrup Fiehn.

Tumor-stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) are prognostic markers in some cancers but with unknown significance in vulvar squamous cell carcinoma (VSCC). This pilot study primarily aimed to develop a digital method for evaluating TSR, TB and TILs in VSCC and secondarily to investigate variation in these factors by p16 status. An independent training set stained with CD3/cytokeratin and CD8/cytokeratin was used to develop a deep learning-based Application Protocol Package (APP) segmenting tissue into background, epithelium, or stroma. TSR was defined as percentage of tumor epithelium relative to total tumor area, and tumor buds were defined as clusters of 1-4 tumor cells. A second APP quantified CD3+ and CD8+ lymphocytes in the intraepithelial and stromal compartments, respectively. The digital algorithms were applied to the study cohort of 41 VSCC cases, achieving satisfactory performance without manual corrections. TSR ranged between 33 and 91% with median of 64%, and median number of buds was 4 (range: 0-48) buds/mm2. Median density and range of CD3+ lymphocytes were 222 (13-2320) cells/mm2 in the intraepithelial and 1978 (397-6683) cells/mm2 in the stromal compartment, respectively. CD8+ lymphocyte counts were lower. There was a tendency towards lower TSR and higher number of buds in p16-negative compared with p16-positive VSCC. Finally, automated measures were compared with manual evaluations showing high concordance. The developed automated method provided precise and objective measurements of TSR, TB and TILs. The algorithms should be validated in a larger cohort and correlated with clinicopathological characteristics and prognosis to determine their clinical relevance.

Keywords: Artificial intelligence; Digital pathology; Tumor budding; Tumor-infiltrating lymphocytes; Tumor-stroma ratio; Vulvar cancer

DOI: https://doi.org/10.1016/j.anndiagpath.2025.152462

Head Neck. 2025 Mar 05.

Combined Tumor Infiltrating Lymphocytes and PD-L1 Status in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.

Catherine T Haring, Joshua D Smith, Sarah M Dermody, Jonathan B McHugh, William R Perry, Collin Brummel, Matthew E Spector, J Chad Brenner, Paul L Swiecicki.

OBJECTIVES: To determine if the assessment of CD8+ tumor-infiltrating lymphocytes (TILs) adds prognostic information to the PD-L1 combined positive score (CPS) in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
METHODS: A retrospective case series was performed of 77 patients with R/M HNSCC between 2003 and 2019. From pre-treatment biopsies, CD8+ TILs and PD-L1 CPS were quantified on a tissue microarray. Associations of biomarkers with overall survival and immune checkpoint inhibition (ICI) response were assessed.
RESULTS: Neither CD8+ TIL counts nor PD-L1 CPS alone were associated with overall survival; however, combined high TILs and CPS ≥ 1 were associated with improved survival compared to low TILS and CPS < 1 (18.5 vs. 10.0 months, p = 0.058). For patients treated with ICI (n = 28), PD-L1 CPS predicted ICI response more strongly than CD8+ TILs.
CONCLUSIONS: In R/M HNSCC, the combination of PD-L1 CPS and CD8+ TILs is a stronger prognostic biomarker for overall survival compared with either biomarker alone.

Keywords: biomarkers; human papillomavirus viruses; immune checkpoint inhibitors; squamous cell carcinoma of head and neck; tumor microenvironment

DOI: https://doi.org/10.1002/hed.28128

Ann Gastroenterol Surg. 2025 Mar;9(2): 359-368

Prognostic relevance of sarcopenia and tumor-infiltrating CD8+ T cells in patients with hepatocellular carcinoma.

Shunsuke Doi, Satoshi Yasuda, Miu Miyashita, Minako Nagai, Kota Nakamura, Yasuko Matsuo, Taichi Terai, Yuichiro Kohara, Takeshi Sakata, Masayuki Sho.

Aim: The relationship between sarcopenia, tumor-infiltrating lymphocytes (TILs), and long-term survival in patients with hepatocellular carcinoma (HCC) has not been investigated. We aimed to evaluate the prognostic relevance of sarcopenia and TILs in patients with HCC.
Methods: We included 351 patients with HCC following liver resection. Sarcopenia was defined based on the skeletal muscle index using computed tomography. Tumor-infiltrating CD4+ and CD8+ T cells, perforin, and granzyme B were examined in liver resection specimens.
Results: Sarcopenia patients had a significantly lower lymphocyte count (p = 0.003), prognostic nutritional index (p = 0.017), and CD4+ and CD8+ T cell counts (p = 0.008 and p = 0.006, respectively). The overall survival (OS) and recurrence-free survival (RFS) rates of sarcopenia patients were significantly lower than non-sarcopenia patients (both p < 0.001). Multivariate analysis revealed that sarcopenia and low CD8 levels were strong independent poor prognostic factors for OS and RFS (both p < 0.001). Regardless of sarcopenia, patients with high CD8 levels had significantly better OS and RFS rates and increased expression of perforin and granzyme B. Particularly, sarcopenia patients with high CD8 levels had much better OS and RFS than those with low CD8 levels and were even comparable to non-sarcopenia patients with high CD8 levels.
Conclusions: Sarcopenia and low CD8 levels are strong independent poor prognostic factors in patients with HCC. Furthermore, sarcopenia patients with high CD8 levels had favorable survival and activated local immunity, suggesting that tumor-infiltrating CD8+ T cells may play a functionally important role in sarcopenia patients.

Keywords: CD8+ T cells; hepatocellular carcinoma; liver resection; sarcopenia; tumor‐infiltrating lymphocytes

DOI: https://doi.org/10.1002/ags3.12875

Cancer Res. 2025 Mar 05.

Single Cell Analyses Reveal a Functionally Heterogeneous Exhausted CD8+ T Cell Subpopulation that is Correlated with Response to Checkpoint Therapy in Melanoma.

Kelly M Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M Haugh, Laura A Huppert, Lauren S Levine, Margaret M Lowe, Michael Alvarado, Markee Micu, Katy K Tsai, Melissa Chow, Meromit Singer, Jason M Schenkel, Arlene H Sharpe, Michael D Rosenblum, Kristen E Pauken, Adil I Daud.

PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or non-responders. While CD8+ tumor infiltrating lymphocytes (TILs) have been associated with immune checkpoint therapy response, there is not a consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX), since TPEX proliferate more in response to PD-1 inhibitors than other exhausted T cell (TEX) subpopulations. However, immune checkpoint inhibitor (ICI) treatment drives TPEX differentiation into other TEX populations that can mediate anti-tumor immunity. These data complicate the ability to identify prognostically important T cell populations in patients that predict ICI treatment response. In this study, we found that advanced melanoma patients with ≥20% of CD8+ TILs co-expressing PD-1 and CTLA-4 (termed CPHi TILs) had better objective response rates and survival following PD-1 monotherapy than those below this threshold. Characterization of the CPHi TIL subset using bulk and single cell RNA sequencing showed that while TPEX-like cells were present within the CPHi subset, they were in the minority of these cells. Rather, the CPHi population was numerically dominated by other subsets, including cycling, terminally exhausted, cytotoxic-like, and/or resident memory-like TEX populations, and a subset enriched for glycolytic genes. Collectively, these data show that CPHi TILs correlate with response in melanoma, but this TIL subset is a heterogenous mix of different subpopulations that may differentially contribute to anti-tumor immunity following checkpoint blockade.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3918