Harnessing senescence to improve cell-based therapies against cancer

Introduction

Senescence is a two-component process comprised of a stable cell cycle arrest and a secretory program named the senescence associated secretory phenotype (SASP), altering the surrounding microenvironment. The program serves as a tumor suppressive mechanism inhibiting the propagation of damaged cells, but the accumulation of senescent cells has been connected to multiple age-associated diseases including cancer.

Therapeutic Implications

Consequently, senescence induction in tumors is not considered a desired therapeutic outcome. Still, therapeutic strategies to treat cancer such as chemotherapy, targeted therapy, and radiotherapy induce senescence at least in a subset of cancer cells.

Proposed Strategy

We here propose to exploit the specific features of senescent cells in the cancer microenvironment to improve therapeutic outcomes in solid tumors. This strategy revolves around the combination of senescence induction with chimeric antigen receptor (CAR) T and NK cells.

Research Objectives

1. Assess Genetic Alterations
   We will first assess the role of specific genetic alterations for the senescence program and resulting reciprocal interactions with CAR expressing immune cells.

2. Translate Knowledge into Designs
   The gained knowledge will be translated into rational designs of CAR T and NK cells to tailor them to the specific senescence context.

3. Innovative Screening and Gene Editing
   Furthermore, our strategies involve innovative screening and gene editing approaches of these cellular-based therapies to:

   • Render them resistant against senescence-inducing therapies, thereby uncoupling desired toxic effects on tumor cells from undesired negative effects on immune cells.
   • Identify single nucleotide variants leading to improved functional persistence of CAR T cells in the senescence context.

Expected Outcomes

Successful completion will lead to promising new therapeutic avenues for a wide variety of malignancies. More broadly, it will result in deeper mechanistic insights into T and NK cell biology as well as immune surveillance mechanisms of senescent and non-senescent tumor cells.