Natural killer immunity and the cancer immunome
Dr Angel Porgador - Ben-Gurion University of the Negev, Beer-Sheva, Israel
Can you outline the first part of your presentation on natural killer cell immunity?
The presentation was divided into two, in the first part I was talking about natural killer cells, natural killer activating receptors, trying to put the focus on the fact that you have isoforms of natural killer activating receptors. Some of the isoforms are lytic and some of them are actually regulatory. So the name natural killer cells with the same receptors could be acting completely different. In the cancer microenvironment actually the in vitro isoforms or the regulatory isoforms of the NK activating receptors are expressed or overexpressed leading to regulatory function, a suppressing function of the natural killer cells, rather than to a killing lytic function of the cells. We have to take it into account when we try to analyse the presence of NK cells in the cancer microenvironment whether it’s a good thing or a bad thing. We also take into account the issue of the isoforms that are expressed, they look like the same receptor but it’s a completely different story.
Can you outline the second part of your presentation on the cancer immunome?
An algorithm that my colleague Eitan Rubin and myself developed at Ben-Gurion University to focus on the cancer immunome. The cancer immunome is basically the status of the immune cells and the immune molecules within the cancer microenvironment; others are calling it immune contexture. It is clear to everybody in the cancer world that the immune contexture, the cancer immunome, is very essential, analysis of the cancer immunome is very essential, very imperative in the decisions about cancer diagnostics, cancer prognosis and the therapeutic approach. So it means that you have to develop accurate and practical methods to immunoscore the cancer immunome. The ultimate immunoscore method would be to immunohistochemistry the cancer looking on the immune cells, to isolate from fresh specimens the immune cells, fresh specimens of the cancer, and to test the phenotype and function.
So that would be the gold standard method to evaluate immunoscore but it’s a tedious method, it’s very hard to implement it accurately in each medical centre, it cannot be centralised. So with my colleague we developed another method to try to immunoscore the cancer immunome and it’s based on RNA expression analysis of resected cancers or biopsies of cancers. RNA expression analysis is becoming a standard method to evaluate the status of the cancer and part of the databank of the caring physician making the decision, the therapeutic decision, for the patient. But most of the analysis that is done of the RNA expression is looking on the cancer genes, the cancer cells, the rest is considered as the garbage, the leftovers, nobody is looking in them. We devised an algorithm to take these leftovers and extract from them an accurate analysis of the immune status, the immunoscore, of the cancer microenvironment and from that we can get a lot of information about prognosis and eventually also therapeutic approach.
So we suggest that using this in focus method you can, in a centralised way, you don’t have to do it in the institute, basically you can send the sample outside, get the RNA expression, do the analysis and basically immunotype the immune contexture of the cancer. The results of this immunotyping should be available to the caring physician and part of his databank of decisions how to take care and how to continue the therapy approach to this patient. So that’s our suggestion.
How was immFocus developed and how does it work?
The main problem was how to normalise the fact that in each biopsy or resected tumour section you have alternate amounts of the immune cells. The alternating amount of the immune cells doesn’t represent difference in unity, it basically represents mostly the randomised ways in which both the biased way in which you are taking the biopsy part, or the resected section, in order to analyse it for RNA expression of cancer. So when we overcome this using the algorithm, this bias, and we overcome the sensitivity using the results of RNA sequencing approach rather than microarrays, we could come with a set of normalising genes to normalise and then extract the immune status of the important immuno-associated genes to analyse the immune status.
What work has been done to validate the method?
We did this work in about 20,000 samples taken from the TCGA, The Cancer Genome Atlas, and now [?? 4:38] we are actually validating it with new samples and not from the TCGA cells that we are doing the RNA sequencing and trying to see whether the set of genes that we actually found for each different cancer can be validated with new testing groups. So that is now this.
What’s the potential for this method?
If you are familiar with Oncotype, that is basically an external service that each physician can send the sample off his patient to this company or service and get more information about the virulence of the specific cancer. We believe that we can generate something like immunotype. Again, you are getting the sample and you are sending your results, similarly to DNA mutation analysis and RNA expression of the [?? 5:28] of cancer. That would be a third wheel of data that can be used in the decision of the physician how to take care of the patient. In particular thinking about immunotherapy, more and more tools of immune checkpoints will be going into the market in the coming years. Eventually the physician will have to take a decision, should they use not just this or this, anti-PD1, anti-CTLA-4 as yesterday but about a list of ten, twenty possible drugs for immunotherapy. So we need this kind of immunotype also to decide on the specific immunotype drug, immunotherapy drug, that he would like to use. So there is a lot of potential now and, of course, later.
Do you have a final take-home message?
The take-home message that we should focus on defining accurate and simplified ways to diagnose the cancer microenvironment and use these ways to define and find better and new tools for therapy, including immunotherapy.
