Impact of the mitochondrial hub on the cytotoxicity and immunogenicity of radiation therapy

Targeting BCL2 and mitophagy to enhance the immunostimulatory effects of
radiation in breast cancer
Radiation therapy (RT) represents a promising tool to convert immunologically “cold”
estrogen receptor-positive (ER + ) breast cancers (BCs) into “hot” lesions that instead
respond to immune checkpoint inhibitors (ICIs), largely reflecting the ability of RT to
elicit BAX/BAK-initiated mitochondrial outer membrane permeabilization (MOMP) in
malignant cells, culminating with cytosolic mitochondrial DNA (mtDNA) accumulation,
CGAS/STING signaling and ultimately type I interferon (IFN) secretion, in support of
anticancer immunity. However, mitophagy has previously been shown to inhibit type I
IFN production in multiple settings, reflecting its ability to efficiently dispose of
permeabilized, mtDNA-releasing mitochondria. Therefore, we observed that MOMP
mediates both mtDNA release (activating type I IFN signaling) and mitophagy (limiting
type I IFN signaling) following RT, and RT-driven mitophagy represents a cancer cell-
intrinsic immunological checkpoint that suppresses immune responses driven by RT, de
facto constituting a target for the development of novel strategies to break through
immunotherapy resistance in ER + BC.

Biography
I am currently a Postdoctoral Associate in Cancer Signaling and Microenvironment at
Fox Chase Cancer Center (Philadelphia, US) in the laboratory of Dr. Lorenzo Galluzzi,
an Associate Professor of Cell Biology Research. Prior to joining the laboratory of Dr.
Galluzzi in March 2022 (first at Weill Cornell Medical College, in New York, then at Fox
Chase), I graduated from Côte d’Azur University (Nice, France) in 2016 with a B.Sc. and
in 2018 with a M.Sc. in Molecular biology, Genetics, and Immunology. Immediately after,
I worked under the supervision of Dr. Yvan-Charvet and in collaboration with Dr. Ricci as
a Ph.D. student in Clinical and Therapeutic Research at the Mediterranean Center of
Molecular Medicine (Nice, France). As a Postdoctoral Associate, I have been focusing
my research on intracellular stress responses, notably the selective autophagic
degradation of dysfunctional mitochondria, commonly known as mitophagy, as a target
for enhancing the ability of radiation therapy to initiate therapeutically relevant
anticancer immune responses in estrogen receptor-positive breast cancer.