T Cell and Tumor Immunotherapy

Dear Colleagues,

There are billions of T cells in the body, and they play a vital role in immunity. However, only a small percentage of T cells exert anti-tumor immune responses. The tumor microenvironment (TME) is an environment that is often infiltrated by T cells which attack tumor cells; however, these very small percentages of T cells encounter a massive amount of tumor-mediated immune suppression when they are infiltrated into the TME.

The overall success rate of immune-checkpoint inhibitors remains low, despite the fact that several of them have been shown to reactivate tumor-reactive T cells. It is indeed possible to improve the clinical outcome and the durability of the response of patients by incorporating new immunotherapeutic drugs, identifying clinical correlates, and applying patient selection criteria.

Overall, through genomic-based biomarkers such as tumor mutational burden (TMB), transcriptome analysis of tumor microenvironments (TMEs), T cell receptor (TCR) diversity, and microbial diversity in tumor microenvironments, we are able to have a much better understanding of tumor microenvironments.

 We believe that by furthering our knowledge on the TME, we can gain a better understanding of how cancer cells and immune cells interact with their environment, and how the immune system can be more effectively activated to fight cancer.

As we prepare this Special Issue, we would like to invite researchers to submit original research articles and reviews that will potentially improve our understanding of tumor microenvironments. We recommend that researchers submit work related to the TME, the diversity of TCRs, the diversity of microbes, and genomics-based correlation studies related to the TME.

Dr. Raghvendra Srivastava
Dr. Anil Shanker
Guest Editors

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• T cell
• tumor microenvironment
• immune cells
• TCR
• microbes
• genomics

Title: Intratumoral T cell migration is enhanced by NLRP3-dependent macrophage - T cell interaction in a pancreatic cancer spheroid model
Authors: Benedikt Slusny#, Vanessa Zimmer#, Elena Nasiri, M. Huber, M. Buchholz, Thomas Gress, Katrin Roth*, Christian Bauer*
Affiliation: 1 Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, Philipps University Marburg, 35043 Marburg, Germany 2 Core Facility Cellular Imaging, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany 3 Institute of Systems Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany 4 DONAUISAR Klinikum Deggendorf, MedizinCampus Niederbayern, 94469 Deggendorf, Germany # contributed equally * contributed equally Corresponding author: Christian Bauer
Abstract: Introduction: Pancreatic cancer is characterized by a highly immunosuppressive tumor milieu with an impaired anti-tumor T cell response (1). Interaction behavior and migration patterns of cytotoxic T cells are pivotal for tumor rejection. Own work has demonstrated that IL-18 receptor signaling of T cells influences intratumoral migration patterns (2). Activated NLRP3 inflammasome of macrophages is a major producer of active IL-18. Aims: Here we investigated the role of NRLP3 activation in myeloid cells for T cell motility in a spheroid model of pancreatic cancer. Material and methods: Murine adenocarcinoma cell line Panc02 was stably transfected with ovalbumin (OVA) and fluorophore H2B-cerulean in order to generate PancOVA H2B‐cerulean tumor cells. Bone marrow-derived macrophages were isolated from tgVenus mice and Corning® Matrigel®-based spheroids were formed from the PancOVA H2B Cerulean pancreatic cancer cells and tgVenus macrophages. NLRP3 activation was performed through stimulation with LPS and nigericin. Cytotoxic T lymphocytes were derived from WT OT-1 or Il18r-/- OT-1 mice, which recognize OVA-derived peptide SIINFEKL as their cognate antigen, and added to the spheroids after one day of spheroid formation. After 4 and 18 hours of coculture 3D microscopy was performed using a light sheet microscope to generate z-stacks. Recording time was 30 minutes. tgVenus macrophages were visualized through expression of yellow fluorescent protein, whereas OT-1 CTLs were stained with CellTracker™ Deep Red. Analysis of interaction and migration was performed by Imaris software. Results: Spheroid formation and characterization of rejection kinetics applying three different cell types (tumor cells, macrophages and CD8+ T cells) was feasible. Close proximity between highly mobile, intra-spheroidal T cells and macrophages was observed, indicating molecular interaction. Rejection of PancOVA spheroids was enhanced when NLRP3-activated macrophages interacted with CD8+ OT-1 CTL, whereas tumor volume reduction was slower when NLRP3 was not activated. When analyzing T cell motility, average speed was increased in spheroids with activated myeloid NLRP3. Arrest coefficient was investigated in spheroids with versus without activated NLRP3 inflammasome. Il18r-/- OT-1 CTLs were used to discriminate strictly IL-18-mediated T cell-intrinsic effects from other effects, such as PD-L1 upregulation on macrophages after NLRP3 activation. Conclusions: Our data indicate a broader role of NLRP3 activation in intratumoral macrophages for T cell motility and rejection kinetics. This extends own previous data on a T cell-intrinsic role of IL-18R deficiency for T cell motility, warranting future mechanistic studies on the interaction of antigen-presenting cells and model-antigen-specific T cells. Literature: 1. Veronika Lutz… Christian Bauer (2023). IL-18 receptor signaling regulates tumor-reactive CD8+ T-cell exhaustion via activation of the IL-2/STAT5/mTOR pathway in a pancreatic cancer model. Cancer Immunology Research, 2023 Apr 3;11(4):421-434. 2. Elena Naisiri… Christian Bauer (2023). IL18 Receptor Signaling Inhibits Intratumoral CD8+ T-Cell Migration in a Murine Pancreatic Cancer Model. Cells Volume 12, Issue 3, 456.