Systems Biology Approaches to Improving Immunotherapeutic Outcomes in Solid Tumors 32 views

Immunotherapy has produced robust and durable responses in many previously hard-to-treat cancers. However, these successes have been difficult to achieve in solid tumors, where immune evasion and suppressive microenvironments pose persistent barriers. Tumors reprogram immune and stromal cells to construct an ecosystem favorable tailored to their growth and to the suppression of immune responses. T cells and macrophages hold strong potential to generate anti-tumor responses but are frequently reprogrammed and rendered dysfunctional within the tumor microenvironment (TME). This dissertation investigates how cell-intrinsic and extrinsic signaling cues shape tumor-resident immune cell states and, in turn, influence immunotherapeutic efficacy. In the first case study, I combine experimental and computational techniques to analyze bispecific antibody-armed activated T cells (BATs) in hormone receptor-positive breast cancer. Through a combination of high-dimensional transcriptomics, multivariate statistical modeling, and mechanistic simulations, I identify a distinct LAG3⁺ CD8⁺ T cell population as a critical driver of tumor cytotoxicity. This work reveals that checkpoint molecule dynamics can diverge from canonical exhaustion signatures and instead indicate therapeutic engagement, offering insights into how T cell states can be harnessed for improved targeting of solid tumors. In the second study, I explore how macrophage glycosylation modulates antibody-dependent cell phagocytosis (ADCP), a key mechanism of anti-tumor monoclonal antibody (mAb) therapy. Reanalysis of primary tumor data, in vitro cytokine polarization experiments, and targeted genetic and enzymatic perturbations reveal that sialylation of FcγR2a—rather than global surface sialylation—directly impairs macrophage ADCP function. This suggests a previously unrecognized layer of immune regulation and presents a tunable axis for enhancing mAb responses in the TME. Together, these studies illustrate the potential of systems immunology approaches in which high-dimensional analysis, mechanistic modeling, and experimental validation are synergistically combined can identify hidden regulators of therapeutic response. By accounting for dynamic immune cell states shaped by the TME, this work provides a conceptual and methodological framework to refine existing immunotherapies and develop next-generation strategies tailored to patient-specific immune contexts.

PHD (Doctor of Philosophy)

Immunotherapy; Systems biology; T cells; Macrophages; Glycosylation; Phagocytosis; Adoptive Cell Therapy

English

2025-07-29