Welcome to the Cytotoxic Immunity and Cancer Cell Death Project Group

Youxian LiProject group leader
Youxian Li
Project group leader

We are a group of professional killers and paralyzers striving to understand how cancer cells can be eliminated or disabled by cytotoxic lymphocytes—the executioner cells of our immune system.

Cytotoxic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), play essential roles in immune surveillance and cancer immunotherapy by recognizing and eliminating malignant cells. Caspase-dependent apoptosis is a well-established mechanism through which cytotoxic lymphocytes eliminate cancer cells. They can initiate apoptosis either by delivering cytotoxic granzymes into target cells through perforin-mediated membrane permeabilization or through the engagement of death ligands, such as Fas ligand (FasL), with their corresponding death receptors, such as Fas, on the target cell surface (Figure 1).

Figure 1: Cytotoxic lymphocytes have been proposed to induce various forms of cancer cell death via the perforin–granzyme axis or the death ligand–receptor axis, the latter of which activates caspase-8 (CASP8). Granzyme B and CASP8 share several downstream apoptotic mediators, including BID (which mediates mitochondrial outer membrane permeabilization) and caspases 3 and 7 (CASP3/7), which orchestrate the apoptotic program. Cytotoxic lymphocytes have also been implicated in several forms of regulated necrotic cell death, including pyroptosis mediated by gasdermins, necroptosis through MLKL activation, and ferroptosis driven by lipid peroxidation. However, it remains unknown whether cytotoxic lymphocytes exert additional, as yet uncharacterized, cytotoxic activities against cancer cells.

It is increasingly recognized that cytotoxic lymphocytes can also induce cancer cell death through non-apoptotic pathways (Figure 1). The discovery and characterization of these alternative death modalities have greatly expanded our understanding of the complex signaling events that occur within cancer cells when they are targeted by cytotoxic lymphocytes. Nevertheless, our understanding remains incomplete, and it is still unclear whether additional pathways contribute to the full spectrum of cytotoxic activities induced by cytotoxic lymphocytes.

Our project team follows two core principles in investigating cytotoxic lymphocyte-mediated cytotoxicity against cancer cells:

  1. We adopt a reductionist approach by systematically deleting death-related genes in cancer cells to disrupt apoptosis and other known forms of cell death. 
  2. We develop simple yet robust killing models that enable unbiased, genome-wide genetic screens to identify cancer cell-intrinsic regulators of cytotoxic lymphocyte-mediated killing (Figure 2). 
Figure 2: Example of a simple and effective killing model for studying CTL-induced cell death events. The mouse mastocytoma cell line P815 is used as the target cell line and naturally expresses mouse IgG receptors (FcγR1 and FcγR3) (left). When coated with a mouse-derived anti-human CD3 (αCD3) antibody, P815 cells can redirect human CTLs to induce target cell killing, thereby bypassing the requirement for TCR–antigen specificity. Targeted disruption of death-related genes enables precise manipulation of cell death pathways in P815 cells (right). The resistance of genetically modified target cells can then be assessed following CTL-mediated killing. This procedure can be repeated to introduce additional gene knockouts, allowing systematic assessment of the contribution of known or previously unidentified genes to cancer cell resistance.

In addition to identifying novel regulators of cancer cell death, we are also interested in uncovering other cytotoxic—or “paralyzing”—effects induced by cytotoxic lymphocytes.

The project is generously supported by the Researcher Project for Young Talents (FRIPRO) under the Ground-Breaking Research Programme, administered by the Research Council of Norway.

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