Regulatory T cells with a single TCR specificity prevent lethal autoimmunity

Foxp3+ regulatory T cells, Tregs, prevent autoimmunity and their total or partial defects can cause lethal or variable autoimmunity. For most part, endogenous ligands recognized by Tregs are not known.

Based on data derived from artificial transgenic models it is suggested that development and maintenance of naturally derived Tregs could be antigen-specific, though it is not known how diverse Treg TCR repertoire should be to keep auto-reactive T cells in check.

To answer this question, Rudensky's research group conducted series of experiment on transgenic mice (G113TgFoxp3^YFP-CreTcra^FL/FL mice) which harbor normal repertoire of conventional T cells but where "all" naturally developed Treg cells would express single TCR specificity (derived from Vβ6+Vα2+ G113 TCR).

Surprisingly, unlike control mice (which did not survive past 4 wk of age), 50% of G113TgFoxp3^YFP-CreTcra^FL/FL mice survived to 4 mo of age (the end point of the experiment) though all of them displayed "visible evidence of significant autoimmunity".

So what does this result tell us? These are quite unexpected results. It would be highly unusual to imagine that a single antigen and single Treg specificity could be sufficient to prevent lethal autoimmunity in 50% of mice. We don't even know the source of the endogenous antigen G113 TCR supposed to recognize.

I personally would rather focus on technical aspect of this result: how robust is TCR modification in G113TgFoxp3^YFP-CreTcra^FL/FL mice? Maybe there is still "leakage" of endogenous TCRalpha chains? I wonder about this because of "50% data". Maybe in those 50% surviving mice Tregs were able to assemble TCR with endogenous TCRalphas?

David Usharauli  

Harnessing donor TCR specificity for cancer immunotherapy

Cancerous tissues harbor protein mutations that can be recognized by immune system as neoantigens. However, when tumor progresses it indicates that either (A) patient lacks T cells with adequate affinity to tumor neoantigens or (B) tumor environment actively suppresses immune response [or both]. 

For example, novel drug class of checkpoint inhibitors targeting CTLA4 and PD1/PD-L1 inhibitory circuits operating in T cells (Keytruda, Opdivo, Yervoy, Tecentriq) work on option B by modulating tumor suppressive micro-environment.

Another approach obviously would be an option A by using engineered T cells expressing tumor specific T cell receptors. Ideally, patient's own T cells can be expanded and re-infused back to attack tumor cells. But, more likely, patient will lack T cells with  adequate affinity to tumor neoantigens due to TCR editing. 

To overcome this limitation, new study published in journal Science suggested to use instead tumor-specific TCRs harvested from healthy donors. Here, the authors led by T cell expert Ton Schumacher, showed that HLA-matched healthy donors contain T cells with sufficient affinity and specificity to recipient's tumor neoantigens (of note, Ton Schumacher is also affiliated with biotech company Kite Pharma).

This study focused on HLA-A*02:01-restricted neoantigens from stage IV melanoma patients. Neoantigens were identified with whole-exome and RNA sequencing and selected for further analysis based on high predicted binding affinity to HLA-A*02:01. Autologous monocyte-derived dendritic cells transfected with mRNA encoding the candidate epitopes and cultured with healthy donor T cells. All 4 healthy donor  T cells specifically detected mutated tumor neoantigens with greater sensitivity.

Tumor neoantigen-specific T cell response was confirmed in epitope pulse experiment using WT or mut epitopes.

Furthermore, when donor T cell derived TCRs were re-introduced by gene transfer, resulting T cells were specific to patient's mut neoantigen and did not recognize, for example, 3rd party tumor cells.

In summary, this short but definitive study points to a growing and undeniable evidence in support for T cell based cancer immunotherapy. By incorporating donor derived TCR specificity this strategy vastly expands the reach of T cells immunotherapy. The challenge remains how to streamline this process (exome sequencing, MHC:peptide binding prediction, TCR identification, TCR transduction and re-infusion) to make it affordable for every cancer patient.  

David Usharauli