bims-tuinly 2024-11-17 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2024–11–17
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Advances and prospects in tumor infiltrating lymphocyte therapy.
An Introduction to Tertiary Lymphoid Structures in Cancer.
Tumor-Infiltrating Lymphocytes in Resected Esophageal and Gastric Adenocarcinomas Do Not Correlate with Tumor Regression Score After Neoadjuvant Chemotherapy: Results of a Case-Series Study.
Prognostic value of tumor-infiltrating lymphocytes in distal extrahepatic bile duct carcinoma.
An in vitro investigation into the cytotoxic impact of antigen-presenting dendritic cell-tumor infiltrating lymphocytes on ovarian cancer cells.
Evaluation of prognostic significance of histopathological characteristics and tumor-infiltrating lymphocytes for pancreatic cancer survival.
NIVO-TIL: combination anti-PD-1 therapy and adoptive T-cell transfer in untreated metastatic melanoma: an exploratory open-label phase I trial.
Rapid parallel reconstruction and specificity screening of hundreds of T cell receptors.

Discov Oncol. 2024 Nov 08. 15(1): 630

Advances and prospects in tumor infiltrating lymphocyte therapy.

Xu Qiu, Shengjun Li, Tianyu Fan, Yue Zhang, Bin Wang, Bei Zhang, Mingzhe Zhang, Li Zhang.

  Tumor-infiltrating lymphocyte (TIL) therapy in adoptive T-cell therapy (ACT) has already caused durable regression in a variety of cancer types due to T-cell persistence, clinical activity, and duration of objective response and safety. TILs are composed of polyclonal effector T-cells specific to heterogenetic tumor antigens, reasonably providing a promising means for tumor therapy. In addition, their expansion in vitro can release them from the suppressive tumor microenvironment. Even though significant advances have been made in the procedure of TIL therapy, from TIL isolation, modification, expansion, and infusion back to the patient to target the tumor, strategy optimization is always ongoing to overcome drawbacks such as a complex process, options for the lineage differentiation status of TILs, and sufficient trafficking of TILs to the tumor. In this review, we summarize the current advances of TIL therapy, raise problem-based optimization strategies, and provide future perspectives on next-generation TIL therapy as a potential avenue for enhancing cell-based immunotherapy.

Keywords:  Adoptive cell therapy (ACT); Immunotherapy; T-cells; Tumor infiltrating lymphocyte (TIL); Tumor treatment

DOI:  https://doi.org/10.1007/s12672-024-01410-5
Methods Mol Biol. 2025 ;2864 1-19

An Introduction to Tertiary Lymphoid Structures in Cancer.

Hye Mi Kim, Tullia C Bruno.

  Immunotherapy has revolutionized therapeutics for cancer patients, which signifies the importance of effective antitumor immunity in combatting cancer. However, the benefit of immunotherapies is limited to specific patient populations and tumor types, suggesting the overt need for new immunotherapeutic targets. Tertiary lymphoid structures (TLS) are ectopic lymph node-like structures that develop at the sites of chronic inflammation such as cancer. TLS are correlated with favorable clinical outcomes across multiple solid tumors and are associated with increased tumor-infiltrating lymphocytes (TILs), particularly effector memory CD8+ T cells. Despite strong clinical data in humans, there are still major knowledge gaps on the function of TLS in cancer. Herein, we highlight the known biology and clinical impact of TLS, which offer further evidence to harness TLS for improved immunotherapeutics.

Keywords:  B cell; Cancer; Follicular dendritic cell; Germinal center; High endothelial venule; Secondary lymphoid organ; T cell; Tertiary lymphoid structure

DOI:  https://doi.org/10.1007/978-1-0716-4184-2_1
Cancers (Basel). 2024 Nov 01. pii: 3694. [Epub ahead of print]16(21):

Tumor-Infiltrating Lymphocytes in Resected Esophageal and Gastric Adenocarcinomas Do Not Correlate with Tumor Regression Score After Neoadjuvant Chemotherapy: Results of a Case-Series Study.

Fotios Seretis, Chrysoula Glava, Spyridon Smparounis, Dimitra Riga, Georgios Karantzikos, Maria Theochari, Dimitrios Theodorou, Tania Triantafyllou.

  Background/Objectives: Adenocarcinomas of the esophagogastric junction and stomach present clinical entities with significant cancer-related morbidity and mortality, often requiring multimodal treatments. Preoperative chemotherapy, mainly the FLOT regimen, is increasingly being utilized in the neoadjuvant setting for the treatment of these malignancies, with varying degrees of tumor response. Methods: We conducted a retrospective, single-institution review on 75 patients operated on for adenocarcinoma of the esophagogastric junction and stomach after neoadjuvant FLOT. We investigated whether tumor response correlates with disease response in lymph nodes examined on surgical specimens. We also investigated the role of tumor-infiltrating lymphocytes (TILs) in correlation with primary tumor response and disease response in lymph nodes on pathological specimens. Results: Our results suggest that TILs correlate in a differential manner with regards to primary tumors versus lymph nodes, thus suggesting that there are different biologic processes in place. Conclusions: Our results provide unique evidence on tumor-infiltrating lymphocytes in the adenocarcinoma histology of the esophagogastric junction and stomach and might be important for further studies.

Keywords:  cancer; chemotherapy; esophageal; gastric; neoadjuvant; tumor infiltrating lymphocytes; tumor regression

DOI:  https://doi.org/10.3390/cancers16213694
ESMO Open. 2024 Nov 06. pii: S2059-7029(24)01739-3. [Epub ahead of print]9(11): 103969

Prognostic value of tumor-infiltrating lymphocytes in distal extrahepatic bile duct carcinoma.

S-Y Jun, S An, S-M Hong, J-Y Kim, K-P Kim.

   BACKGROUND: The assessment of tumor-infiltrating lymphocytes (TILs) has led to the development of various immunotherapies beyond their predictive potential in gastrointestinal malignancies. However, the clinicopathologic and prognostic values of TILs have yet to be well elucidated in distal extrahepatic bile duct carcinoma (DBDC).
PATIENTS AND METHODS: We evaluated stromal TILs (sTILs) and intraepithelial TILs (iTILs) in 405 surgically resected DBDCs to analyze their correlations with overall survival (OS) and recurrence-free survival (RFS) and with clinicopathologic parameters according to the eighth edition of the American Joint Committee on Cancer scheme.
RESULTS: High levels of sTIL density (sTILHigh; >5%) and iTIL count (iTILHigh; >3) were found in 245 (61%) and 74 cases (18%), respectively. sTILHigh was more commonly found in larger tumors (P = 0.048) diffusely involving both intra- and extrapancreatic bile ducts (P = 0.013), in tumors with lower T category (P = 0.002), and in tumors without pancreatic (P = 0.003) or duodenal invasion (P < 0.001). iTILHigh was associated with tumors with papillary or nodular growth pattern (P < 0.001) without perineural invasion (P = 0.006). Both sTILHigh and iTILHigh significantly predicted better OS (P = 0.009 and 0.036, respectively) and RFS (P = 0.003 and 0.026, respectively). sTIL consistently provided prognostic predictability in OS, even when tested with different quantitative cut-offs and prognostically stratified OS (P = 0.006) and RFS (P = 0.005) on multivariate analysis. The survival benefit of sTILHigh persisted regardless of the stage in both OS (P = 0.010 for lower stages I and II and P = 0.001 for higher stages III and IV) and RFS (P = 0.004 and 0.025 for lower- and higher-stage tumors, respectively).
CONCLUSIONS: sTILs were superior to iTILs in predicting survival, and it was shown to be a strong prognosticator for DBDC patients regardless of the stage. The utility of sTILs may extend beyond prognostication to aid in predicting therapeutic responses in DBDC patients.

Keywords:  bile duct; cholangiocarcinoma; distal; prognosis; survival; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.esmoop.2024.103969
BMC Cancer. 2024 Nov 07. 24(1): 1364

An in vitro investigation into the cytotoxic impact of antigen-presenting dendritic cell-tumor infiltrating lymphocytes on ovarian cancer cells.

Shengnan Yang, Junrong Wang, Zhenwu Du, Chunhua Sheng, Qianyu Liu, Xuewei Lao, Donghui Xu, Ying Pan.

   OBJECTIVE: The objective of this study is to develop a novel therapeutic approach for the treatment of ovarian cancer while investigating the role of tumor-infiltrating lymphocytes (TILs) in the context of ovarian cancer therapy. The primary aim is to establish a technical procedure for the isolation of tumor cells, lymphocytes, and dendritic cells (DCs) derived from ovarian cancer tissues or ascites. Subsequently, the focus lies on the generation of dendritic cell-tumor infiltrating lymphocytes (DC-TILs) exhibiting specific cytotoxic capabilities aimed at targeted therapeutic interventions. The cytotoxic impact of DC-TIL interactions on tumor cells was investigated through in vitro experimentation. This research aims to provide fundamental experimental insights for the future clinical advancement of TIL therapy in ovarian cancer.
METHODS: The experimental samples included fresh surgical specimens and ascites specimens procured from three patients (ranging in age from 32 to 75), sourced from the Department of Gynecology at the Third Bethune Hospital of Jilin University. TILs were extracted through in vitro isolation from solid tumor tissues, while primary tumor cells and DCs were obtained from ascites specimens. Tumor-specific antigens derived from patient tumor cells were utilized to stimulate the maturation of DCs. TILs were subsequently co-cultured with antigen-stimulated DC cells. Subsequently, TILs with specific killing effects were obtained, and the cytotoxic impact of DC-TILs on tumor cells was detected in vitro.
RESULTS: (1) TILs were successfully obtained through expansion from the tumor tissue of a patient diagnosed with ovarian cancer. (2) DCs were successfully induced from ascites cells harvested from patients diagnosed with ovarian cancer. (3) TILs significantly enhanced the cytotoxicity of tumor cells following DC stimulation.
CONCLUSION: TILs have the capacity to augment the cytotoxicity directed towards tumor cells following DC stimulation.

Keywords:  Ascites; Dendritic cells; Immunotherapy; Ovarian cancer; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s12885-024-13131-7
Sci Rep. 2024 11 09. 14(1): 27392

Evaluation of prognostic significance of histopathological characteristics and tumor-infiltrating lymphocytes for pancreatic cancer survival.

Kadir Çorbacı, Meryem Gunay Gurleyik, Aylin Gonultas, Fugen Aker, Mehmet Onur Gul, Metin Tilki.

  With a 5-year survival of ˂ 10%, pancreatic cancer is one of the leading causes of cancer-related deaths. Given the role of the distribution of tumor-infiltrating lymphocyte (TILs) subtypes in the tumor and its microenvironment in predicting prognosis, the development of new targeted therapies based on T-cell adaptive response has gained considerable attention. This study aimed to examine the peritumoral spread of TILs and its relationship with other prognostic parameters and survival. This study included 60 patients with pancreatic cancer who had undergone surgery with follow-up between 2011 and 2021. Demographic characteristics, tumor histopathological features, peritumoral TILs counts, and intratumoral programmed cell death protein-1 (PD-1) and programmed death ligand - 1 (PD-L1) positivity were evaluated. Furthermore, overall survival and their efficacy in predicting survival according to TNM stage were analyzed. The number of cluster differentiation-3 positive (CD3 P) TILs increased with advancing pathological T stage. CD3 P and CD8 P TIL counts were higher in patients with peripancreatic fatty tissue invasion. Patients with PD-L1 positivity and higher TIL counts had better survival rates. PD-L1-negative patients with a low CD8 positive/total lymph node count (P/T) ratio had a longer survival. Moreover, patients with poorly differentiated tumors with low CD3 P/T and CD8 P/T ratios had a longer survival. The CD3 P/T and CD8 P/T ratios were compatible with the automatic and manual measurements. Age, tumor differentiation, N stage, and peritumoral TIL count and subtype, when evaluated together with the presence of PD-L1 in the tumor tissue, may have prognostic significance for survival in patients with pancreatic cancer.

Keywords:  CD3; CD8; PD-1; PD-L1; Pancreatic cancer; Survival; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1038/s41598-024-79342-x
Acta Oncol. 2024 Nov 07. 63 867-877

NIVO-TIL: combination anti-PD-1 therapy and adoptive T-cell transfer in untreated metastatic melanoma: an exploratory open-label phase I trial.

Jean-Matthieu L'Orphelin, Ugo Lancien, Jean-Michel Nguyen, Francisco J S Coronilla, Soraya Saiagh, Julie Cassecuel, Lise Boussemart, Anne Dompmartin, Brigitte Dréno.

BACKGROUND AND PURPOSE: In patients with metastatic melanoma who respond to anti-PD-1 therapy, the proliferation of intra-tumour CD8+ T cells is directly correlated with the clinical response, making tumour-infiltrating lymphocytes (TILs) a treatment of interest in combination with a PD-1 inhibitor, which is the undisputed gold standard in the management of metastatic melanoma. The aim of this trial was, therefore, to evaluate the safety and efficacy of sequential combination therapy consisting of nivolumab (a PD-1 inhibitor) and TILs adoptive T cells in patients with metastatic melanoma.
MATERIALS AND METHODS: We performed an exploratory, prospective, single-centre, open-label, non-randomised, uncontrolled phase I/II study. We enrolled 10 previously untreated patients with advanced melanoma. The treatment regimen was neoadjuvant anti-PD-1 therapy followed by 2 injections of TILs and a second sequence of anti-PD-1 therapy.
RESULTS AND INTERPRETATION: Among the four patients who received the autologous TILs + nivolumab combination, three (75%) achieved an objective response (two achieved a partial response [PR] at the end of the study, two achieved a complete response [CR]), and one achieved a CR at the end of the study. Among these three patients, one had a PR, and two had stable disease (SD) after the nivolumab course and before any TILs administration, reinforcing the importance of the tumour response after TILs injection. These responses were persistent, ranging from 9 months to 3.4 years.

DOI: https://doi.org/10.2340/1651-226X.2024.40495
Nat Protoc. 2024 Nov 08.

Rapid parallel reconstruction and specificity screening of hundreds of T cell receptors.

Alexander B Afeyan, Catherine J Wu, Giacomo Oliveira.

The ability to screen the reactivity of T cell receptors (TCRs) is essential to understanding how antigen-specific T cells drive productive or dysfunctional immune responses during infections, cancer and autoimmune diseases. Methods to profile large numbers of TCRs are critical for characterizing immune responses sustained by diverse T cell clones. Here we provide a medium-throughput approach to reconstruct dozens to hundreds of TCRs in parallel, which can be simultaneously screened against primary human tissues and broad curated panels of antigenic targets. Using Gibson assembly and miniaturized lentiviral transduction, individual TCRs are rapidly cloned and expressed in T cells; before screening, TCR cell lines undergo combinatorial labeling with dilutions of three fluorescent dyes, which allows retrieval of the identity of individual T cell effectors when they are organized and tested in pools using flow cytometry. Upon incubation with target cells, we measure the upregulation of CD137 on T cells as a readout of TCR activation. This approach is scalable and simultaneously captures the reactivity of pooled TCR cell lines, whose activation can be deconvoluted in real time, thus providing a path for screening the reactivity of dozens of TCRs against broad panels of synthetic antigens or against cellular targets, such as human tumor cells. We applied this pipeline to systematically deconvolute the antitumoral and antiviral reactivity and antigenic specificity of TCRs from human tumor-infiltrating lymphocytes. This protocol takes ~2 months, from experimental design to data analysis, and requires standard expertise in cloning, cell culture and flow cytometry.

DOI: https://doi.org/10.1038/s41596-024-01061-4