• What limits current in vitro models from accurately reflecting the complex tumor microenvironment and in vivo bispecific antibody activity?
• Designing in vitro assays that better predict targeted efficacy and potential for off-target effects within the TME
• Innovative in vitro approaches or technologies that hold promise for predicting the in vivo behavior and therapeutic potential of bispecific antibodies in immuno-oncology?​​

• Spatial biology has recently exploded—during what stages of IO drug discovery are you using spatial biology and what questions are you answering?
• Spatial biology is a new frontier and is constantly evolving—how do you balance ever-pursuing the latest technologies, versus committing to and developing specific technologies?
• Integration of spatial biology into IO drug discovery can require huge investments of computational, wet-lab, and financial resources—what are the biggest hurdles you’re encountering, and how are you navigating these challenges?​

Spatial transcriptomics and single-cell sequencing provide unprecedented insights into the tumor microenvironment, revealing critical determinants of immunotherapy response. This presentation explores how mapping gene expression at tissue and cellular levels identifies key interactions and pathways driving cancer outcomes. In large B cell lymphoma, we implicated a CCL8/CCL13+ macrophage population in resistance to both CAR T cell therapy and chemoimmunotherapy. For diffuse midline glioma, we combined complementary spatial technologies to achieve unprecedented resolution of this challenging tumor environment. These approaches reveal new therapeutic vulnerabilities and resistance mechanisms across cancer types.

Single-cell RNA sequencing and multiplex imaging of lung tumors revealed two CAF populations, MYH11+ and FAP+, driving T cell exclusion. These CAFs form dense barriers with distinct matrix compositions, collagen IV and XI/XII respectively, compared to T cell permissive CAFs. This study identifies unique CAF-mediated T cell marginalization mechanisms, suggesting targeted therapies to improve immunotherapy efficacy in T cell excluded tumors.

In our pioneering, under-review work, we construct a physiologically relevant ex vivo colorectal cancer (CRC) interface, unveiling two groundbreaking findings. Firstly, we establish that it is the oxygen gradient—not merely the absolute oxygen levels—that dictates CRC proliferation and architecture. Furthermore, this model facilitates an exploration into how these hypoxic gradients enables novel studies on epithelial-microbiota cocultures and tumor-T cell interactions.

Multiomics approaches, integrating genomics, transcriptomics, proteomics, and metabolomics, are crucial for biomarker discovery in immunotherapy. This presentation will highlight how these integrated analyses identify predictive and prognostic biomarkers, improving patient stratification and treatment response prediction. We will explore the power of combining diverse data types to enhance our understanding of immune responses and therapeutic efficacy.

Immunotherapy is transforming cancer treatment, with cytotoxic T cells as the primary target. However, resistance mechanisms have highlighted the crucial role of myeloid cells in shaping therapeutic outcomes. To advance the next generation of immunotherapies, it is essential to address the immunoregulatory functions of myeloid cells, particularly in solid tumors. Key myeloid antigen-presenting cells—macrophages, dendritic cells (DCs), and monocytes—exhibit significant phenotypic and functional diversity. Our research focuses on characterizing this diversity within solid tumors to uncover novel cellular and molecular targets for immunotherapy, which I will describe in this seminar.

This presentation examines the functional effects of cancer cell phagocytosis on tumor macrophages. We used single-cell transcriptomic profiling in genetic mouse tumor models to identify tumor macrophage gene expression changes associated with cancer cell phagocytosis. We have now applied related signatures to identify human macrophages that have specifically phagocytosed tumor cells in human non-small cell lung cancer (NSCLC) transcriptomics datasets. Analysis of spatial transcriptomics datasets has allowed us to understand this phenotype in human NSCLC tumors and learn what cell states preferentially co-localize with these macrophages that have the potential to present tumor antigens. Insights into these dynamic interactions may help identify therapeutic targets for modulating macrophage behavior and enhancing anti-tumor immunity.

NKG2D is an activating receptor expressed by all human NK, CD8T, subsets of gamma-delta T cells, and activated macrophages, The ligands of NKG2D are generally absent in healthy tissues. This uniqueness has attracted the vitality in harnessing NKG2D pathway for cancer therapy, with efforts on targeting NKG2D ligands and utilizing NKG2D for cell-based therapy. I will discuss the unrecognized complexity of this pathway and potential viable strategies.

Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. Current allogeneic donor-derived products require lymphodepletion to prevent immunologic rejection of donor cells, but this can negatively impact combination therapies where a robust T cell response is desired. We discuss the scientific data and initial clinical results using our allogenic NK cell therapy (SNK02) in solid tumors without lymphodepletion.