Investigating the roles of NF-κB subunits as master regulators of CD8+ T-cell function in cancer immunity and immunotherapy.
Worldwide Cancer Research
Cancer Center of Lyon
Cancer progression is greatly influenced by a delicate balance between tolerance to and immune response against tumors. The recent success of immunotherapies such as checkpoint-blockade therapies, demonstrates that this balance can be shifted effectively towards enhanced anti-tumor immunity, to delay or even stop cancer progression, particularly by enhancing the function of CD8+ T cells. However, only a fraction a patients respond to these regimens, and the molecular mechanisms that drive the response and resistance to immunotherapies are largely unknown. The transcription factor NF-kappaB (NF-kB) has been implicated in the regulation of T-cell function. However NF-kB is in fact a family of transcription factors composed of 5 distinct subunits; due to the lack of suitable tools, the contribution of individual subunits of NF-kB to CD8+ T-cell biology has never been addressed. In this application, we propose to investigate the exact roles of NF-kB subunits that control CD8+ T-cell function in cancer immunity. We will use unique mouse models carrying ablation of NF-kB subunits specifically in mature CD8+ T cells, CRISPR-based gene edition in primary human cells and high-throughput sequencing analyses. Based on our previous publications and preliminary data, we hypothesize that the activation of selective NF-kB subunits orchestrates CD8+ T-cell biology and underlies the clinical response to checkpoint-blockade therapies. Importantly, these studies may reveal specific NF-kB subunit activities that can be targeted by novel therapeutics to enhance T-cell function alone or in concert with existing immunotherapies.
2.1 Biological and endogenous factors