Background
Adoptive T cell therapy (ACT) harnesses the immune system to recognise tumour cells, achieving
unprecedented results in curing cancer. However, metabolic constraints imposed by the tumour
microenvironment (TME) suppress CD8+ T cell (CTL) anti-tumour responses by reshaping their metabolism.
Our findings demonstrated that lipids play a previously unappreciated role in modulating CTL fate and
function driven by metabolic changes.
Hypothesis
Our in vitro lipid screening pointed at Palmitic Acid (PA) as a major negative regulator of CTL activity. PA
prevents CTL activation and effector functions by disrupting their mitochondrial fitness through up-regulation
of sphingosine kinase 2 (SPHK2). We propose SPHK2 inhibition as a potent therapeutic approach to energise
CTL and improve their anti-tumour functions.
Aims
The overarching goal of this proposal is to correct CTL dysfunction to improve ACT efficacy for cancer therapy.
This will involve:
1. Decode SPHK2 role in CTL fate and function, revealing mechanistic details;
2. Validate SPHK2 inhibition in CTL, to enhance ACT efficacy for PDAC and other solid tumors.
Experimental Design
We will deeply phenotype CTL activation, differentiation, effector functions and metabolic fitness after tuning
SPHK2 in normal activating versus metabolic stressed conditions (AIM1). Subsequently, metabolic dysfunction
will be reverted using ex vivo SPHK2 inhibition and "metabolically fit" CTL will be tested for their ability to
mediate tumour rejection in a preclinical model of pancreatic cancer, lymphoma and neuroblastoma. Finally,
we will test this approach on other tumour types refractory to immunotherapy (AIM2).
Expected Results
This proposal will highlight the link between metabolic dysfunction in CTL and SPHK2, outlining its role in CTL
biology and providing initial evidence to translate its ex vivo inhibition to immune-based cancer therapies. We
will demonstrate how SPHK2 exerts its function by altering CTL lipid metabolism and mitochondrial function,
which prevent CTL to adapt to metabolic changes imposed by TME. We predict that targeting SPHK2 will
empower CTL with superior metabolic fitness and enhanced persistence at the tumour site, which will result in
long-lasting immune-surveillance. Our results will mark a step toward the use of immunotherapy on PDAC as
well as other solid tumors, on which it has failed so far.
Impact On Cancer
ACT has revolutionised the treatment of haematologic malignancies, though the use of ACT in solid tumors,
which represent 90% of human cancer, is still in its early stages. Thus, as we move forward to the next
breakthrough in cancer treatment, it is of pivotal importance to develop new strategies to empower CTL with
the ability of overcoming the obstacles imposed by the TME. Previously, we have defined SPHK2 as a novel
therapeutic target to potentiate ACT efficacy by enhancing T cell long-term functionality, metabolic fitness and
preventing exhaustion. If we can successful leverage SPHK2-inhibition to tweak CTL metabolism, we will enable
CTL to perform better in a hostile microenvironment. While illuminating a still blurred side in CTL biology, our
team is equipped with expertise and infrastructures to really take this discovery to clinic and, potentially, have
a clinical impact on patients' lives in the near future.