Short course in immuno-oncology

It is well established that the main cells of the immune system that are either assisting or directly involved in attacking cancer cells are a specific subset of dendritic cells (DCs), type 1 macrophages (M1Φs), natural killer cells (NKs), gamma-delta antigen receptor expressing T lymphocytes (γδTs), natural killer T lymphocytes (NKTs), (tumour-antigen specific) CD4 expressing type 1 helper T lymphocytes (Th1s) and (tumour-antigen specific) CD8 expressing cytotoxic T lymphocytes (CTLs)1. Of these, CTLs are the most crucial cells, since they have the ability with their T-cell (antigen) receptor (TCR) to specifically recognize tumour cells (through the expression of tumour specific antigens on these cells), bind to them and kill them through the release of cytotoxic compounds.

For the generation of activated CTLs, a specific subset of activated DCs is essential. These specific DCs have the unique ability to process antigens (including tumour-antigens) in a specific way and present these antigens by so-called cross-presentation to CD8 expressing lymphocytes and to generate a Type I immune response, which response is required for the ultimate killing of tumour cells. This specific subset of activated DCs are called cDC1s (conventional (migratory) DC causing Type I immune responses).

As part of this Type I immune response, tumour-antigen presenting cDC1s stimulate the generation of activated tumour-antigen specific Th1s and CTLs. With the assistance of such generated Th1s, these CTLs mature further and multiply extensively to become real ‘fighting machines’ which migrate from the location where they were generated by cDC1s (often in a lymph node) to the tumour. Inside the tumour they recognize tumour cells that express tumour-antigens by using CTL’s tumour-antigen specific TCR with which they bind to the tumour cells. Such binding leads to the activation of the CTL, which then starts to release their cytotoxic molecules (cytotoxins), such as perforins and granzymes. Perforins make holes in the outer membranes of the tumour cells through which the granzymes (highly aggressive enzymes) enter the inside of the tumour cells and kill them.

Of the above other listed immune cells involved in anti-cancer activity, NKs likely play the second most important role2. In contrast to CTLs they can recognize tumour cells in the absence of expressed tumour-antigens. Through specific receptors NKs can bind to tumour cells and recognize tumour-related changes in the molecular make-up of molecules expressed by tumour cells (e.g. reduction of classical MHC class I molecules or increase of nonclassical MHC class I-related molecules caused by DNA damage and cell stress). Such changes activate NKs into (i) the production of perforins and granzymes and (ii) the triggering of a cascade of special ‘suicide’ molecules within the tumour cells; both pathways leading to the death of the tumour cell. Activated cDC1s also play a crucial role in further assisting activated NKs into becoming aggressive ‘fighting machines’.

Activated CTLs, Th1s, γδTs, NKTs and NKs are the typical end products of an orchestrated Type I immune response caused and lead by activated cDC1s playing the essential role of conductor of the orchestra. A hallmark molecule of a Type I immune response is gamma interferon (IFN-γ), a molecule (cytokine) that is abundantly produced and released by activated CTLs, Th1s, γδTs, NKTs and NKs. IFN-γ not only plays an important role in optimizing the activation of these cells and M1Φs, it also inhibits Type II immune responses (which mainly generates antibodies as end products) and, very importantly, it causes changes in tumour cells that make them more ‘visible’ for the immune system.

1Vesely MD et al. Annual Review of Immunology 2011 29:235-271
2Canter RJ and Murphy WJ. Journal for Immune Therapy of Cancer 2018 6:79-81