Date of Award
Doctor of Philosophy (PhD)
Dennis E. Discher
Immunotherapies harness the power of the immune system, broadly, to identify, suppress, or otherwise control disease progression. Potent immune checkpoints, such as PD-1/PD-L1, CTLA4, and here, CD47-SIRPα restrain immunity in normal regulation to protect healthy ‘self’ cells, yet can become dysregulated in the progression of diseases. Antibody-based blockade of such checkpoints has emerged as a powerful tool to retrain and re-energize immune surveillance, but significant barriers to efficacy and safety remain. CD47-SIRPα is the macrophage immune checkpoint that enables macrophages, a first line of defense in innate cellular immunity, to discriminate ‘self’ vs. ‘foreign’, which many cancers utilize to evade clearance. Consequently, CD47 is now a clinical target for antibody-based blockade in early and late phase clinical trials in many liquid tumors and some solid tumors. However, clinically targeting a ubiquitously expressed surface marker presents numerous challenges, including a large antigen sink, on-target but off-tumor clearance, and mass permeation of solid tissues that are yet to be answered (Chapter 1 and Chapter 4). Here, we demonstrate that efficacy of molecular and cell-based therapies targeting CD47-SIRPα requires complete ablation of signaling and a pro-phagocytic signal to drive tumor-specific macrophage phagocytosis in solid tumors (Chapter 2). We further delineate and provide evidence for a novel phenomenon of “cooperative phagocytosis” in these tumors, whereby macrophages that are maximally activated along the CD47-SIRPα paradigm, work together to disrupt solid tumor adhesions and durably eliminate tumoroids in vitro and tumors in vivo (Chapter 3). Finally, we highlight a significant role for macrophages as potent immune effectors to clear tumors and induce a de novo, endogenous antibody response that strengthens macrophage phagocytosis and cooperativity with high tumor antigen-binding and -specificity (Chapter 3). These results position macrophages as potent immune effectors in solid tumors with the potential to overcome long-standing challenges in immuno-oncology (Chapter 5).
Andrechak, Jason Christopher, "Leveraging Macrophage Immune Checkpoint Blockade To Link Innate And Adaptive Immunity Against Solid Tumors" (2022). Publicly Accessible Penn Dissertations. 5502.