Saturday, February 14, 2015

Cancer-bacterial relationship: how wrong focus can spoil everything

New concepts are only useful if they can explain something or predict something. Sometimes scientific idea is good but using wrong model to test it could produce negative impression.

Here is the one example for a such scientific approach. This paper was published in journal Immunity few days ago. This study identified bacterial component, Fap2, that can protect cancer cells from NK cell cytotocixity through TIGIT interaction. This concept of bacteria protecting tumors against immune system is very interesting, so I decided to analyse it.

Initially the authors showed FITC labeled Fusobacterium nucleatum (F. nucleatum) strain 23726 could bind both hematopoietic and epithelial cancer cell line. Surprisingly, these cell lines pre-incubation of F. nucleatum strain 23726 showed resistance to NK cell natural cytotoxicity (but there was no effect on IFN-γ or TNF-α production). This inhibition of NK natural cytotoxicity was specific for F. nucleatum strains since Escherichia coli lacked this effect.

The authors speculated and then showed that inhibition of NK natural cytotoxicity by F. nucleatum strains could be due to its interaction with inhibitory receptor TIGIT.

Indeed, transfection of TIGIT-negative NK cell line with human TIGIT could reduce its natural cytotoxicity against EBV-transformed B cell line.

Similar reduction of NK cell natural cytotoxicity were observed when primary human NK cells were used, though effect was minimal when using human colorectal carcinoma cell line, RKO.

Next, the authors were able to show the actual clinical isolates of F. nucleatum strain recovered from human colon adenocarcinoma samples could inhibit NK cell cytotoxicity.

Using F. nucleatum transposon-based insertion-inactivation mutant library the authors showed that inhibition of NK cell natural cytotoxicity was reversed with Fap2 mutation.

Additional the authors showed that Fap2 mutant F. nucleatum strains failed to induce IL-2 production from cell line transfected with human TIGIT.

Fap2 mutant F. nucleatum strains also failed to interact with purified human TIGIT.

Finally, the authors showed F. nucleatum strains could (1) inhibit TIL cytoxocity against autologous melanoma cells in a Fap2-dependent manner and (2) inhibit peptide-specific T cell IFN- response.

In summary, these results show that F. nucleatum strains could interact with human TIGIT and this interaction reduces NK cell cytotoxicity in a Fap2-dependent manner but has no effect on NK derived IFN-γ or TNF-α production. Strangely, it appears that Fap2 inhibited both T cell cytoxicity and IFN-γ production.

In my opinion since the authors argue in the beginning that F. nucleatum strains are mostly found in human colon adenocarcinoma tissue, but showed that Fap2 effect on NK cytotoxicity against colorectal carcimona cell line, RKO, is negligent, it puts the significance of this finding into question.

David Usharauli

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