The pros and cons of dying tumour cells in adaptive immune responses

Therapeutics based upon using the adaptive immune system to fight against tumours have become the most promising in the field. Increasing evidence has shown that multiform cell death-mediated events play vital roles in regulating adaptive immune responses within tumours, thus providing potential antitumour therapeutic targets. In their recent Review article (Dying cells actively regulate adaptive immune responses. Nat. Rev. Immunol. 17, 262–275; 2017)¹, Albert et al. discussed the active signals generated during cell death processes and their roles in facilitating the priming of antigen-specific CD8⁺ T cells. These immunogenic processes represent an ideal tumour–immune interaction and offer a favourable immune basis for conventional therapeutics such as chemotherapy and radiotherapy.

However, Albert et al. neglected the fact that dying tumour cells may also regulate adaptive immune responses in another way: namely, by prompting T cell exhaustion. Previous studies have shown that dying tumour cells can release tumour antigens, which can serve as damage-associated molecular patterns (DAMPs), into the tumour microenvironment^2,3. These tumour antigens persistently stimulate adaptive immune cells such as CD8⁺ and CD4⁺ T cells and induce the latter to acquire a dysfunctional state called T cell exhaustion⁴. Unlike tolerance to a self-antigen, T cell exhaustion is a dysfunctional state characterized by reduced cytokine production and compromised cell-killing ability⁵. Mounting evidence has shown that T cell exhaustion contributes significantly to tumorigenesis and may induce failure of antitumour therapeutics⁶. Therefore, besides actively regulating antitumour adaptive immune responses, dying tumour cells may also compromise antitumour immunity by inducing T cell exhaustion.

The authors highlighted the importance of type I interferons (IFNs), which can be released by dying cells as a type of 'inducible DAMP (iDAMP)' in treatment-associated immunogenic cell death. However, several studies have suggested that type I IFN signalling has contradictory roles in adaptive immune response. For example, Wang et al. showed that the upregulation of IFNβ expression in dendritic cells promoted antigen presentation but compromised T cell priming⁷. Another study showed that elevated levels of type I IFNs during type 1 diabetes triggered lymphocyte exhaustion and disabled lymphocyte-mediated immune responses⁸. In a tumour-bearing mouse model, IFNα augmented programmed cell death 1 (PD1) expression on antigen-specific CD8⁺ T cells and thus significantly inhibited T cell-mediated immunity⁹. In a chronic infection model, blocking type I IFN signalling decreased T cell exhaustion and viral replication¹⁰. Therefore, type I IFNs might also impair adaptive immunity by inducing T cell exhaustion in tumours.

In summary, besides the effects of dying cells on adaptive immunity that are detailed by Albert et al., dying cells might have another effect on adaptive immunity: that is, inducing T cell exhaustion.