Tissue retention of antigen-specific resident memory T cells

In recent years research in memory T cell response showed that secondary response to peripheral antigen challenge is driven mostly by locally-residing, tissue resident memory T cells (T_RM). Such studies are important to understand how vaccines affect development of T_RM (previously, main focus was on memory T cells residing in lymphoid tissues, such as spleen and lymph nodes).

Few studies suggested that virus induced T_RM cells could migrate out and reside in tissues not directly affected by virus [i.e. Ag-independent manner]. However, immune response to different viruses can differ fundamentally from each other. For example, new report in Journal of Experimental Medicine (JEM) showed that skin infection with vaccinia virus (VacV, a benign relative of smallpox) instructs development and retention of local T_RM in an antigen-specific manner.

In mice, infection with VacV by skin scarification produces local infection and induction of virus antigen-specific T cell response is local as well.

Importantly, accumulation of CD8 T cells within infected tissue was indeed antigen-specific, and not driven by local virus-induced inflammation per se.

Secondary antigenic challenge confirmed that T_RM response was restricted to local tissue previously infected with virus carrying the same antigen.

In summary, this study showed that in case of VacV infection tissue retention of T_RM cells was antigen-dependent and occurred locally at the site of primary viral challenge.

David Usharauli

Cish is a NK cell checkpoint inhibitor

This week several science news outlets spotlighted new study from Nature Immunology showing anti-tumor effect of Cish deficient NK cells. This study showed that Cish deficient NK cells are hyper-responsive to its canonical cytokine IL-15 and show improved control of experimental tumors.

I analysed this study to determine if the buzz was deserving. In my view this study is in fact two independent [and not connected] studies put together artificially. The finding that Cish deficient NK cells have superior anti-tumor behavior is based on non-physiological experimental model.

First part of this study deals with cytokine sensitivity of Cish deficient NK cells. This is exclusively in vitro experiments. It does show that Cish deficient NK cells are hyper-responsive to NK cell canonical cytokines such as IL-15, or IL-12/IL-18 combo [and other activatory receptors].

Second part of this study, however, is completely dissociated with IL-15 story and jumps directly to tumor protection experiments with WT or Cish deficient NK cells. These experiments showed that Cish deficient mice are resistant to exogenously injected tumor cells and this protection depended on asiolo-GM1+ cells and IFN-γ.

Finally, the authors showed that adoptive transfer of Cish deficient NK cells into NK-deficient hosts (Ncr1^Mcl1Δ/Δ mice) also provided protection against i.v. injected melanoma cell metastasis.

In summary, this study proposed that Cish functions as a checkpoint inhibitor for NK cells.

My view:

(A) It is not clear whether Cish deficient NK cells alone is sufficient for anti-tumor effect [it is independent of CD8 T cells, but CD4 T cells involvement was not tested].

(B) It is not clear what role cytokines such as IL-15 or IL-12/18 play in vivo in Cish deficient mice.  

(C) One of the major differences between NK and T cells is that NK cell effector functions are not regulated in an antigen-specific manner but rather by sensing signaling balance between activatory and inhibitory membrane receptors [functions like a rheostat].

During ontogeny individual NK cell undergoes its own "adjustment" to its environment and can even "tolerate" naturally arising tumor cells. This is why experimental tumor models when tumors are injected exogenously, and appear in the body out of the blue so to speak, do not recapitulate natural interaction with NK cells and easily could produce biased, non-physiological response from first-time encountering NK cells. The more physiological tumor models will be to use spontaneously arising mouse tumor models.

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