Mechanisms underlying inhibition of melanoma brain metastases upon immune checkpoint targeting

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Melanoma is the deadliest form of skin cancer. Once melanoma has spread throughout the body, it is known as metastatic melanoma. At this stage melanoma becomes very difficult to treat and the standard treatment is effective only in a very small proportion of patients. In recent years new drugs have been approved for the treatment of metastatic melanoma. These drugs inhibit the molecules called PD-1 and CTLA-4 that are present on a subpopulation of white blood cells called T lymphocytes. Inhibition of PD-1 and CTLA-4 helps the immune system to attack the cancer. Although these drugs significantly extend lives of melanoma patients, complete responses upon combined inhibition of PD-1 and CTLA-4 are seen only in 11.5 % of the patients. It is therefore important to gain a better understanding of how these drugs work in order to be able to develop approaches that further improve their efficacy.Notably, the immune system works in different ways within different organs in the body. It is therefore important to understand how the drugs targeting PD-1 and CTLA-4 work within the organs to which melanoma most commonly spreads. Our goal is to understand how the efficacy of PD-1 and CTLA-4 blockade could be improved in the brain, to which cancer spreads in up to 60% of metastatic melanoma patients. The resulting tumours are called brain metastases (BrM) and they are particularly difficult to treat. In comparison to the melanoma in general, we know very little about BrM; this is because - despite their high incidence - patients with BrM are mostly excluded from clinical trials and BrM are experimentally strongly understudied. Notably, brain has a very distinct cellular composition and the presence of the blood-brain barrier restricts access of drugs and immune cells into the tumour. Ignoring these specifics of the brain poses a danger that - despite a progress in the treatment of melanoma in other parts of the body - treatment of BrM once again lacks behind and BrM become a limiting factor in patient survival. It is therefore critical to identify the mechanisms involved in the action of drugs targeting PD-1 and CTLA-4 in BrM in a timely manner.There are to date no experimental studies investigating how the drugs targeting PD-1 and CTLA-4 work in BrM. To study the latter, we established an in vivo model of melanoma BrM and demonstrated that a combined targeting of CTLA-4 and PD-1 significantly inhibits growth of BrM and prolongs the survival. This was mainly mediated by a subpopulation of T lymphocytes called Cytotoxic T lymphocytes (CTLs) and by another type of white blood cells called natural killer cells. CTLs accumulated in tumours following therapy. Therefore our goal is to understand how CTLs travel to BrM and to determine how they kill cancer cells in the context of this therapy. We also observed increased accumulation of white blood cells of so-called myeloid lineage in tumours. We therefore aim to determine whether these cells are also required for activity of drugs targeting PD-1 and CTLA-4 in the brain.Understanding how CTLs travel to BrM will enable the development of strategies that can enhance CTL accumulation within the tumour in the brain and are therefore expected to potentiate the efficacy of therapy targeting PD-1 and CTLA-4. If our study determines that white blood cells of myeloid lineage are involved in inhibition of BrM following targeting of PD-1 and CTLA-4, this will provide a rational for improved therapies combining targeting of PD-1/CTLA-4 and myeloid cells. At least part of the newly gained knowledge is expected to be applicable to melanoma at sites other than the brain. Thus, the knowledge emerging from the proposed research has a potential to contribute towards improved outcomes of patients with BrM and those with metastatic melanoma in general.