Tuesday, June 2, 2015

Melanoma-intrinsic β-catenin signaling prevents local DCs activation and anti-tumor T cell-priming

A high-profile scientific literature in immunology for the past 2 years is dominated by papers related to tumor immunotherapy. This probably has to do with the clinical successes of various immunotherapeutic approaches seen in recent years and the shift in funding for cancer research.

Here is new paper from journal Nature discussing immune response to tumor. The authors showed that melanoma-intrinsic β-catenin signaling prevents DC-mediated anti-tumor T cell priming.

By profiling melanoma tumor samples based on CD8 T cells numbers the authors observed that melanoma samples with low T cell numbers were enriched for mutations in genes involved in β-catenin pathway (gain-of-function or loss-of-function mutations).  

Using mouse model of spontaneous tumor induction, the authors confirmed that presence of active β-catenin signaling prevented T cell recruitment to the tumor tissue.

Experiments with adoptive transfer of nominal antigen (SIY)-specific T cells indicated that active β-catenin signaling in tumors prevented T cell priming.

Next, the authors showed that β-catenin signaling in tumor prevented recruitment of CD8α+/CD103+ DCs, a DC subset responsible for cross-priming. This suggested that lack of infiltration of tumors by T cells may have to do with lack of T cell priming by DCs.

Indeed, the authors showed that intra-tumoral injection of in vitro generated wild-type DCs activated with Poly(I:C) could restore T cell tumor infiltration.

Finally, the authors showed that adoptive transfer of wild-type of DCs in combination with antibodies against CLTA4/PD-L1 restored anti-tumor effect against β-catenin active tumor.

In summary, these results indicate that melanoma with constantly active β-catenin pathway inhibits anti-tumor T cell priming. Of note, β-catenin pathway plays a role in DCs maturation. It is not clear whether β-catenin pathway in DC per se was a contributing factor in this mouse model (separately from tumor).

David Usharauli

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