How the genetic landscape of a tumor governs the tumor’s response to immunotherapy remains largely elusive. Here, we established a direct in vivo CRISPR/Cas9 gene editing methodology to assess the immune-modulatory capabilities of 573 putative cancer genes associated with altered cytotoxic activity in human cancers. Using KrasG12D- and BrafV600E-driven mouse lung cancer models, we identify Adam2 as our top immune enhancing genes.

Spatial profiling technologies like hyper-plex immunostaining in tissue, spatial transcriptomics have the potential to enable a multi-factorial, multi-modal characterization of the tissue microenvironment. Scalable, quantitative methods to analyze and interpret spatial patterns of protein staining and gene expression are required to understand cell-cell relationships in the context of local variations in tissue structure. Objective scoring methods inspired by recent advances in statistics and machine learning can serve to aid the interpretation of these datasets, as well as their integration with other companion data, like genomics. In this talk, we will discuss elements of spatial profiling from multiple studies, as well as tools from statistics and machine learning in the context of these problems.

Immunotherapies have shown limited efficacy in glioblastoma. While radiographic tumor contact with the lateral ventricle correlates with worse outcomes; the extent to which ventricle proximity impacts immunobiology in the tumor microenvironment remains unknown. Using CyTOF profiling and machine learning approaches, we identify the suppressive impact of ventricle contact on anti-tumor immunity in the brain and reveal potential clinically actionable immune targets and patient stratification methods for glioblastoma.

Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of cell fate and controls proinflammatory signaling downstream of multiple innate immune pathways. Leveraging the Proteolysis targeting chimera (PROTAC) technology, we developed a first-in-class RIPK1 degrader, which sensitizes ICBs by not only overcoming the intrinsic resistance in cancer cells but also activating a B cell subpopulation to contribute to antitumor immunity.

Genomic and functional genomic approaches have revolutionized our understanding of the role the immune system plays in human health and disease; however, our knowledge of the post-translational drivers of immune dysregulation in diverse pathologies is still incomplete. This talk will describe an integrated chemical proteomic and phenotypic screening approach that enables interrogation of structural and functional changes in the proteomes of immune cells and identification of small-molecule covalent protein degraders.

Immunomodulatory drugs (IMiDs) are molecular glues that can modulate the immune system by targeting certain proteins for degradation by remodeling the surface of cereblon, a component of an E3 ubiquitin ligase. In this talk, we demonstrate that five IMiDs currently used in the clinic, or are currently in clinical trials, can stimulate T helper cell polarization towards different phenotypes. We also address the cereblon-independent effects of the IMiDs on T helper cells.

A critical immune pathway being brought to light by research at Palleon is sialoglycan-mediated immune modulation. Sialoglycans are novel therapeutic targets that are upregulated in many cancers and play an immune-suppressing role. Palleon has designed therapeutic candidates able to degrade sialoglycans, as well as tools to measure a patient’s specific tumor sialoglycan signature. Palleon is now testing its enzymatic sialoglycan degrader in a Phase 1/2 study.

High impact respiratory viruses such as pathogenic beta-coronaviruses and influenza viruses, pose an ongoing global health threat to humans. There is a critical need for physiologically relevant, robust, and ready-to-use in vitro cellular assay platforms to rapidly model the infectivity of emerging respiratory viruses. We are using a panel of 3D platforms of varying complexity, paired with scRNAseq and cytokine profiling, in order to characterize high impact respiratory viral infections in physiologically relevant lung models.