Abstract
This dissertation investigates the myeloid cell circuits that enforce immunosuppression in the tumor microenvironment and limit responses to immune checkpoint blockade. Using genetically engineered mouse models, germ-free and microbiota manipulation approaches, and a humanized inhibitory receptor transgenic system, we identify two complementary axes through which myeloid cells restrain anti-tumor immunity — one systemic and microbiota-dependent, one local and extracellular matrix-dependent. In the first, we demonstrate that TREM2 functions as a systemic brake on gut-tumor immune crosstalk: TREM2 deficiency combined with anti-PD-1 treatment reprograms intestinal macrophages, expands the commensal bacterium Ruminococcus gnavus, and drives migration of gut-imprinted TNF-producing CD4⁺ T cells to the tumor bed in a microbiota-dependent manner. In the second, we show that fibronectin deposited within the metastatic niche engages LILRB4 on tumor-infiltrating myeloid cells, locking them in a suppressive state through attenuation of JAK–STAT1 signaling, and that therapeutic blockade of this interaction reprograms the myeloid compartment toward an ISG-high, type I interferon-dependent anti-tumor state. Together, these findings define spatially distinct myeloid checkpoints operating at the systemic and local levels, identify R. gnavus as a candidate probiotic adjuvant for immunotherapy, and establish the Fn–LILRB4–IFNAR axis as a stromal immune checkpoint with direct therapeutic implications for fibronectin-rich solid tumors.
Committee Chair
Marco Colonna
Committee Members
David DeNardo; Gregory Longmore; Gwendalyn Randolph; Robert Schreiber
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Cancer Biology)
Document Type
Dissertation
Date of Award
4-28-2026
Language
English (en)
DOI
https://doi.org/10.7936/gqv3-pn32
Author's ORCID
https://orcid.org/0000-0002-2579-5140
Recommended Citation
Khantakova, Darya, "Reprogramming of Myeloid Cells for Anti-Tumor Immunity" (2026). Arts & Sciences Graduate Student Theses and Dissertations. 3773.
The definitive version is available at https://doi.org/10.7936/gqv3-pn32