Friday, January 23, 2015

Gene signature of tumors under immune pressure

Tumor is a tissue undergoing homeostasis-resistance turnover. Animal studies suggested that immune system can detect and sometimes eliminate tumor. In humans, however, the data are more complex and there is no clear answer, especially for solid tumors.

Since experimentation on human subjects ad libitum is obviously not an option, the scientists are constantly developing indirect, ex vivo approaches to study human tumor immunology. Advances in omics science made it possible to analyze large data set to find a clinically-relevant correlations between tumor-specific signatures.

This is exactly what this new paper published in journal Cell tried to do. This group led by Nir Hacohen at the Massachusetts General Hospital, has analyzed human tumor samples for gene signatures looking for evidence for their adaptation to local anti-tumor immune response. Such knowledge, if proven reliable, could be helpful  in determining the effectiveness of tumor immunotherapies. 

The authors has decided to focus on cytolytic gene signature (granzyme A and perforin) as a readout for tumors sensitivity to local immune response. Initial analyses showed that tumors varied in their expression of cytolytic signature. 

The authors reasoned that one reason for difference in cytolytic gene signature could be due to presence of tissue-specific viruses, frequently associating with tumors, like HPV virus for cervical cancer tissues. 

Additionally, the authors found there was evidence for depletion (reduction) of neo-epitope expression from predicted number of HLA-binding non-silent mutations, implying these tumors were under immune pressure.

Correspondingly, the authors identified several mutated genes that were enriched in tumors under immune pressure. One of these genes was caspase 8, a well-known member of cell death pathway.

Finally, the authors found there was positive or negative correlation between high cytolytic gene signature and amplification of gene regions containing immuno-regulatory genes such as PD-L1, PD-L2 and IDO1, IDO2.

In summary, these results provided indirect evidence suggesting that human immune system can detect tumor neo-epitopes and mount cytolytic response to eliminate it, thus exerting pressure on tumor cells to develop inhibitory counter-measures. Targeting these pathways could benefit the development of effective immunotherapeutic approaches.

Now there are few limitation to this study. First, cytolytic signature molecules, granzyme A and perforin, can be evidence of immune suppression rather than immune activity. Second, since the authors do not provide tumor patients survival data, it makes hard to argue for usefulness of these results for clinical application.

David Usharauli

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