Variation and Therapeutic Potential of Immune Cell States

Abstract

The immune system plays a pivotal role in safeguarding the body by targeting pathogens, parasites, and abnormal self-cells, including cancerous ones. Immune cells exhibit significant heterogeneity, which is shaped by their development during hematopoiesis, signaling environments, tissue contexts, and disease. This diversity offers numerous opportunities for therapeutic interventions. This dissertation explores the interplay between immune cell variability and therapeutic potential across diverse contexts, emphasizing their roles in hematopoiesis, cancer immunotherapy, and plasma cell dyscrasias. In the context of cancer immunotherapy, we dissect the cellular and molecular mechanisms driving immune-related adverse events (irAEs) and therapeutic efficacy. Using anti-CD40 immunotherapy in mice, we demonstrate that TH1-promoting cytokines IL-12 and IFN-γ are central to liver toxicity, with Kupffer cells and neutrophils driving inflammatory damage, while dendritic cells and CD8+ T cells mediate tumor control. These findings illuminate pathways to decouple immunotherapy efficacy from associated toxicities, providing strategies to mitigate irAEs while preserving therapeutic benefits. Separately, an in-depth analysis of neutrophil heterogeneity reveals a Sellhi neutrophil subset with an ISG signature whose infiltration is linked to tumor control in immunotherapy. This study provides strategies to harness neutrophils to enhance immunotherapy outcomes. We further investigate the bone marrow as a site in both health and disease, focusing on plasma cell dyscrasias such as AL amyloidosis. By combining single-cell RNA sequencing, clonal profiling, and microenvironmental analysis, we uncover unique transcriptional states and niche dynamics associated with disease. Complementing this, we present an early effort to construct an atlas of hematopoietic variation across healthy individuals, revealing demographic and environmental influences on immune cell composition. Together, these studies bridge fundamental immunology with clinical applications, advancing our understanding of immune cell variability in health, disease, and therapeutic innovation.