Date of Award
2020
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Graduate Group
Immunology
First Advisor
Andy J. Minn
Second Advisor
Carl H. June
Abstract
Immune therapies have significantly improved outcomes for cancer patients with
poor prognosis, but mechanisms that underlie response or resistance to therapy remain
elusive. Inflammatory cytokines such as interferon-gamma (IFNG) augment immune
function yet also promote T cell exhaustion through inhibitory ligands such as PDL1. How
these opposing effects are integrated in the tumor microenvironment is unclear. We show
that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs)
in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by
exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection.
In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of
innate immune cells, promoting tumor clearance. Thus, interferon signaling in cancer cells
and immune cells oppose each other to establish a regulatory relationship that limits both
adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation
of this relationship is associated with response to immune checkpoint blockade
independent of tumor mutational burden.
In addition to these suppressive mechanisms, tumor infiltration and antigen loss
are common mechanisms that limit effectiveness of T cell responses in solid tumors, in
particular chimeric antigen (CAR) T cells. Delivery of pattern recognition receptor agonists
is one strategy to improve immune infiltration and prime adaptive immunity; however,
targeting these agonists to immune cells is challenging, and off-target signaling in cancer
cells can be detrimental as described above. Here, we engineer murine CAR-T cells to
deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5-dependent interferon
signaling. RN7SL1 is deployed in extracellular vesicles and preferentially transferred to
intratumoral immune cells. Unlike other RNA agonists, RN7SL1 restricts development of
myeloid-derived suppressor cells and decreases TGFB expression. In dendritic cells, it
fosters DC subsets with anti-viral and costimulatory features. Consequently, endogenous
effector-memory CD8 T cells expand, while exhausted T cells contract. Armed with the
ability to activate endogenous immune responses, these CAR-T cells effectively reject
solid tumors and tumors with CAR antigen loss by drawing on our insights into tumor
resistance mechanisms.
Recommended Citation
Johnson, Lexus, "Cellular Localization Of Inflammatory Signaling As A Determinant Of Tumor-Immune Biology" (2020). Publicly Accessible Penn Dissertations. 4154.
https://repository.upenn.edu/edissertations/4154
Included in
Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons