Tuesday, September 1, 2015

Bypassing "do not eat me" signal could unleash anti-tumor T cell response

CD47 receptor on healthy cells serves as a "do not eat me" signal when engaged by its ligand, SIRPα, on phagocytic macrophages. As cells ageing they express less of CD47 and become targets for scavenger macrophages. In 2013, a study was published that showed that anti-CD47 antibody therapy could prime anti-tumor CD8 T cell response via cross-priming phagocytic macrophages

This time, however, a new paper in Nature Medicine suggested that anti-tumor effect of anti-CD47 antibody therapy is mediated via dendritic cell-enabled cross-priming of CD8 T cells involving intracellular DNA recognition by STING-IFNα pathway. Lets examine the data.

First, the authors showed that the growth of both lymphoma (A20) or solid tumors (MC38) were inhibited in wild-type mice after injection of mouse anti-CD47 monoclonal antibody.

This anti-tumor effect of anti-CD47 antibody was dependent on CD8 T cells.

In addition, using CD11c-DTR BM chimera, the authors showed that anti-tumor effect of anti-CD47 antibody was dependent on CD11+ dendritic cells.

Further experiments revealed that IFNα singaling in CD11+ dendritic cells played an important role.

Finally, the authors showed that tumor growth in mice deficient for intracellular DNA sensing signaling pathway, called STING (tmem173), was not inhibited by anti-CD47 antibody.

In summary, these results suggest the following scenario: anti-CD47 antibody injection facilitates uptake of tumor DNA and associated antigens by DCs. Within DCs, tumor DNA activates STING-IFNα pathway and allows anti-tumor CD8 T cell priming.

From this study it is not clear whether anti-CD47 antibody has any direct cytotoxic effect on CD47+ tumor cells. Also it is not clear how tumor antigen and DNA is delivered to DCs. The authors did not mention anything about any side effects of anti-CD47 therapy either (CD47 is expressed ubiquitously).

There is one figure in this paper that is problematic. While in all other figures anti-CD47 antibody treatment alone has a clear anti-tumor effect in wild-type mice, in Fig. 6a, injection of anti-CD47 antibody alone in wild-type mice shows no anti-tumor effect at all (A20 cells and antibody injection on day 12, 17).

I could not find any explanation in this paper for this major discrepancy. This could question the reliability of anti-CD47 treatment.

David Usharauli  

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