What is CTL? CTL refers to a cytotoxic T lymphocyte cell.
How is CTL activated?
A 4-step process of CTL activation: In response to cancer cells, the innate and adaptive arms work together in coordinated and sequential events. Cytotoxic T cells (or CTL) express CD8 marker on the cell surface - CTLs are also called CD8+ T cells - and are the chief immune cells to take care of cancer cells via a 4-step process mediated by dendritic cells (or DC):
- Step 1: DC spots cancer cells by a surface antigen, and packages it to MHC-I.
- Step 2: Travels to a local lymph node and presents the “cargo” to CTL which serves to prime CTL. (DC functions here as an antigen-presenting cell [APC] for CTL activation.)
- Step 3: The primed CTL is now fully informed and ready for an encounter with the cancer antigen-MHC-Class I complex now displayed on the cancer cell surface.
- Step 4: Once CTL makes contact with the cancer cell, the cancer cell is doomed for apoptosis, also called programmed cell death.
Thus, CTL recognizes and kills cancer cells via the T cell receptor (TCR) binding of cancer-unique sequences presented on HLA-A, HLA-B, or HLA-C using three sets of cell-cell interactions:
- Between DC and cancer cells where HLA Class I molecules (specifically, HLA-A, HLA-B, HLA-C) play the indispensable role of serving as the vehicle to display the cancer antigen.
- Between DC and CTL where HLA on DC carries the cancer antigen and presents it to CTL. The T cell receptor (TCR) recognizes the cancer antigen and CTL becomes primed.
- Between CTL and cancer cell where the cancer cell presents its own antigen or HLA to TCR on CTL.
- Activated CTL secretes two enzymes of perforin and granzyme B. Perforin pokes holes on the surface of the cancer cell to allow granzyme B to enter the cancer cell.
- Granzyme B then initiates the apoptotic cascade to fragment and kill cancer cells. The details of CTL activation mediated by dendritic cells are illustrated in Figure 2.
A recent publication by Mass General Hospital reports observations of how CTL manages to extend its survival time within the tumor environment.3 Specifically, CTL relies on a type of cytokine called interleukin 15 (or IL-15) secreted by dendritic cells (DC) for extended survival to enable CTL to sustain its action against cancerous cells. Interesting to see the dual function of DC as an antigen-presenting cell (APC) for CTL activation and as a cytokine producer to prolong CTL.
The ideal versus the reality: It is important to point out that what is described in Figure 2 is the ideal scenario of APC-mediated and CTL-operated cancer cell destruction. In the real world of a complex cancer landscape, cancer cells often manage to escape stringent immune surveillance via multiple mechanisms. A major mechanism involves how cancer cells capitalize on CTL’s HLA restriction and accordingly engage in altering HLA Class I molecule (specifically, HLA-A, HLA-B, HLA-C) expression to hold CTL in check. In the next topic, details of this cancer molecular trick in selective cancer types will be reviewed.
