Tumor Immune MicroEnvironment Facility (Scientific Core)

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The Tumor Immune MicroEnvironment (TIME) Lab is a research hub within the Center for Immuno-Oncology (CIO) at the National Cancer Institute. Our mission is to deeply investigate how immune cells interact with tumors and how these interactions are influenced by immunotherapy. By studying tissue samples from patients and preclinical models, we aim to uncover new ways to make cancer treatments more effective-paving the way toward durable responses and potential cures. ________________________________________ Investigating Interleukin-12 (IL-12) in Cancer Immunotherapy IL-12 is a protein naturally made by certain immune cells that helps activate both innate and adaptive immune responses. Because of its powerful effects, IL-12 has been tested in various cancer immunotherapy trials. The TIME Lab has made significant contributions to understanding its role. Clinical Applications In a study with Dr. Jonathan Hernandez, we analyzed tumor samples from patients with metastatic colorectal cancer treated with IL-12 therapy (PDS01ADC) alongside liver-directed chemotherapy. Immune analysis revealed that many tumors were rich in CD8 T cells, particularly in immune-dense regions, but most of these cells were not actively killing cancer cells. However, a large portion expressed TCF1, a marker linked to long-term immune memory. One patient had a complete response, correlating with high levels of these "stem-like" T cells. In contrast, patients whose tumors progressed showed a sharp increase in T-regulatory cells, which can suppress immune responses. In another clinical study, we investigated how IL-12 affects Kaposi sarcoma-a rare cancer-in partnership with Dr. Ramya Ramaswami. Using advanced staining and nanostring technologies, we analyzed immune cells at multiple time points. While CD8 T cell numbers remained steady, responders showed an increase in CD44, a molecule tied to T cell activation. Non-responders, on the other hand, exhibited more immune-suppressive cells like CTLA4+, FOXP3+, and CD66b+ cells, all linked to poor immune function and worse outcomes. In collaboration with Ankyra Therapeutics, we studied ANK-101, a new IL-12 therapy designed to stay localized in tumors, reducing side effects. In patient samples, tumors that didn't respond showed higher levels of immune-suppressive cells called MDSCs. This highlights the role of the tumor microenvironment in determining who benefits from IL-12 therapies. ________________________________________ Preclinical Discoveries Using IL-12 and Combination Therapies The TIME Lab also conducts detailed analyses of preclinical tumor models to uncover how experimental treatments influence the immune landscape. In mouse models of oral cancer (MOC), we studied the effects of ANK-101 alone and in combination with Entinostat, a drug that alters gene expression to help immune cells function better. When both drugs were used together, we observed large, organized clusters of immune cells known as tertiary lymphoid structures (TLSs)-a promising sign of strong, coordinated immune activity. These structures appeared more developed in the combination-treated tumors, suggesting synergy between the therapies. Our earlier work (Fabian et al., JITC 2024) showed similar immune structures in tumors treated with ANK-101 combined with anti-PD1 therapy and cisplatin. Collaborating with Drs. Gameiro and Minnar, we also saw these structures in CT26 colon tumors treated with PDS01ADC, anti-PD1, and N803 (a cytokine-based immunotherapy). To better characterize these immune clusters, we developed new staining panels that identified key immune cell types like B cells, CD8 T cells, dendritic cells, and key markers such as CXCL13 and TCF1. This work confirmed that combination therapies can create highly active immune areas in tumors. Our findings-showing increased numbers of cytotoxic T cells, helper T cells, B cells, and dendritic cells-support the idea that generating TLSs may be critical for long-lasting responses to immunotherapy. A manuscript describing this research is currently under review at JCI. ________________________________________ Exploring the Immune Landscape in Thymic Cancer In a study led by Dr. Arun Rajan, we explored immune responses in patients with thymic epithelial tumors treated with PT112, a drug that causes tumor cells to die in a way that activates the immune system. We focused on macrophages, which can either help or hinder the immune response. In samples from one patient who responded to treatment for over a year, we found an increase in immune-suppressive M2-type macrophages along with more CD8 T cells and natural killer cells. Additional samples from this trial are under review. This work was presented at the 2025 AACR Annual Meeting. ________________________________________ Supporting CAR-T Cell Therapy in Breast Cancer To aid the CIO's cell therapy research, we're helping develop a new CAR-T cell treatment targeting ACTL8, a protein found in triple-negative breast cancer. We are optimizing staining methods to validate the presence of ACTL8 in tumor cells using multiple antibodies and cell lines. This project is ongoing, but foundational for advancing this new therapeutic strategy. ________________________________________ Enhancing Immune Responses in Prostate Cancer In a published study (Lassoued et al., JITC 2025), we evaluated immune responses in patients with localized prostate cancer treated with a vaccine called PROSTVAC and the checkpoint inhibitor nivolumab. After treatment, we found significantly more CD4 and CD8 T cells in and around tumors. Over 90% of patients showed at least a twofold increase in these immune cells. Importantly, immune-suppressing T-regulatory cells remained low. This dual treatment showed a stronger immune activation than the vaccine alone. ________________________________________ Conclusion The TIME Lab at the NCI is at the forefront of understanding how immunotherapies reshape the tumor environment. Through a combination of clinical collaborations and rigorous preclinical models, we are uncovering how to make immune-based treatments more effective and targeted. Our goal is to translate these insights into better therapies-and better outcomes-for patients with cancer.