Discovered how Acute Myeloid Leukemia escape immune recognition after BM transplantation

 Bone marrow transplantation from a donor – called allogenic transplantation – is one of the most effective treatment for acute myeloid leukemia (AML), thanks to the anti-tumor capacity of the transplanted immune system. However, following transplantation, leukemia cells often develop strategies to evade immune recognition, resulting in the disease relapse.  A group of researchers from Ospedale San Raffaele and Scientific Institute in Milan investigated the mechanism behind this evasion process by analyzing cancer cells and T lymphocytes, before and after bone marrow transplantation. By looking at both genetic and epigenetic modifications, scientists unveiled new survival strategies implemented by tumor cells as a result of the immunological pressure after transplantation. The findings, published today in two different papers in Nature Medicine and Nature Communications , could have direct implications for the clinical treatment of AML relapses. The study was carried out thanks to the support of the Italian Association for Cancer Research (AIRC) and was coordinated by Luca Vago, head of the Immunogenetics, Leukemia Genomics and Immunobiology research Unit, Chiara Bonini, deputy director of the division of Immunology, Transplantation and Infectious Diseases and Fabio Ciceri, head of the Hematology and Bone Marrow Transplantation clinical Unit. 

Group of researchersGroup of researchers

The anti-tumor effect of allogenic bone marrow transplantation is at least in part driven by incompatibilities between the donor's immune system and the patient's cancer cells. Donor T lymphocytes recognize patient-specific molecules – called HLA – expressed on leukemia cells and identify them as foreign elements, to be attacked and therefore eliminated. In case of tumor relapses, however, the transplanted immune system seems unable to recognize the tumor and act accordingly, why? 
In 2009 the same group of researchers authoring today’s papers, found a partial answer to the question: sometimes a genetic mutation in the DNA of leukemic cells changes the HLA molecules on their surface to make them more similar (and therefore invisible) to the transplanted immune system. After 10 years, that discovery has already influenced the clinical practice: when a relapse is explained by a genetic mutation in HLA genes, physicians know that a second bone marrow transplant by a different donor is the best therapeutic option. However, this phenomenon does not explain all the relapses observed. 

In the studies published today researchers at San Raffaele revealed two other mechanisms – this time epigenetic – exploited by tumor cells to survive: on the one hand, they reduce the expression of HLA molecules on the surface, thus hiding from patrolling lymphocytes; on the other hand, they increase the presence of specific immunosuppressive receptors that tell lymphocytes to slow down their activity and end up turning off the immune response. 
 «Understanding which of these mechanisms is behind a specific relapse will allow physicians to give patients a specific treatment, based on the escaping strategy deployed by cancer cells», explains Luca Vago. «The final goal is to have a personalized approach to relapses, which will improve therapeutic outcomes by finding a new rationale in using the therapeutic options already available». Indeed, if the relapse is caused by decreased expression of HLA molecules, one solution could be to induce a controlled inflammatory state, which would then raise the level of interferon in the blood, a molecule we know promote the expression of HLA molecules. On the contrary, if the relapse is explained by the tumor turning off the activity of T lymphocytes, patients could be treated with immune checkpoint inhibitors, drugs that re-activate T lymphocytes and turn back on the immune response. In both case, making the wrong treatment choice could not only be ineffective, but even detrimental. 
These findings pave the way both for a personalized approach to relapses and for new strategies of early diagnosis: «We found that the presence of inhibitory processes in memory T cells in the bone marrow actually precedes the relapse full manifestation», explains Chiara Bonini. «Which means that, in the near future, by analyzing patients' lymphocytes derived from the bone marrow and by looking for signs of inhibitory activity, we will be able to know in advance of an upcoming relapse, even if still no cancer cell can be found in the patient’s blood». 
The research was possible thanks to the funding received from the Italian Association for Cancer Research (AIRC) and from the Ministry of Health

Toffalori C. et al., Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation, Nature Medicine, 2019

Noviello M. et al., Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCR, Nature Communications, 2019