Immune system is, in principle, capable of tumor recognition and rejection. So far, however, few mechanisms have been described which explain this process (ATP or HMGB1 release, for example).
This week two new, back to back papers in journal Immunity provided additional data regarding tumor detection by immune cells. I am going to review them individually.
Initially, the authors observed that mice deficient either in intracellular DNA sensing molecule STING or IRF3 failed to prime antigen-specific CD8 T cells against B16 melanoma cells expressing SIY antigen. In contrast, mice deficient in MyD88, TRIF, TLR4, TLR9, ATP receptor, or RNA-sensing MDA5/RIG-I showed normal CD8 T cell priming.
In vivo tumor growth experiments show that the absence of STING and IRF3 significantly diminished mice ability to control both the growth of spontaneously, MCA-induced sarcoma as well as B16 melanoma expressing SIY antigen. In contrast, TRIF-deficient mice showed no impairment. For some reason, the authors presented tumor growth data from different experiments in different Y scale. Not the best practice.
To understand the mechanism behind tumor sensing, the authors exposed WT BmDCs to various B16 cells source (live, heat inactivated, irradiated, etc). Interestingly, only pure DNA from B16 cells induced IFN-beta secretion in BmDCs and that only in presence of membrane-opener lipofectamine.
However, this IFN-beta response was abolished in STING-deficient BmDCs.
Interestingly, both in vitro and in vivo, DNA derived from normal splenocytes could induce IFN-beta response in CD11+ dendritic cells, though not as strong as tumor DNA. This response in vivo was STING dependent.
Additional experiments show that STING deficiency affected CD8 T cell survival post cell division.
Mechanistically, failure of tumor-specific CD8 T cell accumulation was linked to deficient DCs activation in STING-deficient mice.
Finally, the authors showed that compared to WT mice, anti-tumor efficacy of clinically relevant anti-CTLA4/anti-PDL1 injections was reduced in absence of STING, though anti-CTLA4/anti-PDL1 injections still showed significant, almost 2-fold delay in tumor growth in STING-deficient mice.
The authors pointed out that they do not yet know how tumor DNA is able to gain access to DCs cytosols in vivo but not in vitro. In fact, in vitro, DNAs are notoriously hard to put inside cells, even with lipofectamine or with other transfection methods. So much so, that many labs and companies have moved into a RNA field as an alternative model for antigen delivery. But even with RNAs, we don't know much either. Such knowledge will be the basis for a rational design of tumor vaccines.