Elucidating type 1 conventional dendritic cell-dependent anti-tumour immune responses in brain metastases
Lead Research Organisation:
University of Leeds
Department Name: School of Medicine
Abstract
Melanoma is the most aggressive 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 used to be frequently excluded from clinical trials and BrM are experimentally strongly understudied. Notably, brain has a very distinct cellular composition, with the blood-brain barrier hindering access of drugs and molecules, and it lacks lymphatic vessels that play an important role in initiation of immune responses. 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 only very few studies investigating how the drugs targeting PD-1 and CTLA-4 work in BrM. To study this, we previously 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). For T lymphocytes to develop into CTLs that can kill cancer cells, they need help from another population of white blood cells called dendritic cells (DCs). DCs take up molecules derived from cancer cells and present these to T lymphocytes, which induces their activation into CTLs. There are different types of DCs. Our studies demonstrated that type 1 conventional dendritic cells (cDC1s) are required for the control of tumour growth in BrM. We therefore aim to determine how exactly are cDC1s involved in the control of BrM growth following therapy targeting PD-1 and CTLA-4, and how cDC1s in the brain differ from those outside the brain.
Understanding how cDC1s support immune responses against BrM will enable the development of strategies that can enhance the ability of cDC1s to support CTLs in their attack against cancer and are therefore expected to potentiate the efficacy of therapy targeting PD-1 and CTLA-4. 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, as well as other cancers.
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 used to be frequently excluded from clinical trials and BrM are experimentally strongly understudied. Notably, brain has a very distinct cellular composition, with the blood-brain barrier hindering access of drugs and molecules, and it lacks lymphatic vessels that play an important role in initiation of immune responses. 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 only very few studies investigating how the drugs targeting PD-1 and CTLA-4 work in BrM. To study this, we previously 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). For T lymphocytes to develop into CTLs that can kill cancer cells, they need help from another population of white blood cells called dendritic cells (DCs). DCs take up molecules derived from cancer cells and present these to T lymphocytes, which induces their activation into CTLs. There are different types of DCs. Our studies demonstrated that type 1 conventional dendritic cells (cDC1s) are required for the control of tumour growth in BrM. We therefore aim to determine how exactly are cDC1s involved in the control of BrM growth following therapy targeting PD-1 and CTLA-4, and how cDC1s in the brain differ from those outside the brain.
Understanding how cDC1s support immune responses against BrM will enable the development of strategies that can enhance the ability of cDC1s to support CTLs in their attack against cancer and are therefore expected to potentiate the efficacy of therapy targeting PD-1 and CTLA-4. 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, as well as other cancers.
Technical Summary
Combined anti-PD-1/anti-CTLA-4 (PC) therapy has shown a great promise in melanoma, with a superior efficacy in brain metastases (BrM) as compared to anti-PD-1 monotherapy. However, only 11.5% of the patients in general show a complete response after PC therapy. Thus, a better understanding of the underlying mechanisms is required to enable the improvement of therapeutic efficacy, including in BrM that develop in up to 60% of metastatic melanoma patients and are associated with very poor prognosis.
Immune-specialized environment of the brain parenchyma is among other factors caused by the lack of lymphatic vessels and immunosuppressive characteristics of the brain tumour draining lymph nodes. Our previous data demonstrate that anti-tumour immune responses in BrM are also affected by the systemic immunity that is generated by the presence of extracranial cancer lesions, a situation unique to BrM, requiring understanding of molecular mechanisms in this specific context.
Using mouse models of melanoma and breast cancer BrM, which faithfully mimic clinically observed intracranial responses to PC combination, we demonstrated that type 1 conventional dendritic cells (cDC1s) are required for anti-tumour immune responses in the brain in the absence of therapy and following PC blockade. cDC1-dependent control of tumour growth differed between tumours in the brain and those at the extracranial site in the skin or mammary fat pad. Building upon these findings, our goals are to elucidate how the systemic immunity induced by the presence of extracranial cancer lesions affects cDC1s and cDC1-dependent responses in the brain, how the latter differ between the brain and extracranial sites, and how this effects site-specific CD8+ T cell responses. We will use a combination of tumour transplantation and hematogenous BrM models, human scRNAseq data and human BrM tissue. This is expected to reveal potential strategies for the enhancement of anti-PD-1/anti-CTLA-4 efficacy.
Immune-specialized environment of the brain parenchyma is among other factors caused by the lack of lymphatic vessels and immunosuppressive characteristics of the brain tumour draining lymph nodes. Our previous data demonstrate that anti-tumour immune responses in BrM are also affected by the systemic immunity that is generated by the presence of extracranial cancer lesions, a situation unique to BrM, requiring understanding of molecular mechanisms in this specific context.
Using mouse models of melanoma and breast cancer BrM, which faithfully mimic clinically observed intracranial responses to PC combination, we demonstrated that type 1 conventional dendritic cells (cDC1s) are required for anti-tumour immune responses in the brain in the absence of therapy and following PC blockade. cDC1-dependent control of tumour growth differed between tumours in the brain and those at the extracranial site in the skin or mammary fat pad. Building upon these findings, our goals are to elucidate how the systemic immunity induced by the presence of extracranial cancer lesions affects cDC1s and cDC1-dependent responses in the brain, how the latter differ between the brain and extracranial sites, and how this effects site-specific CD8+ T cell responses. We will use a combination of tumour transplantation and hematogenous BrM models, human scRNAseq data and human BrM tissue. This is expected to reveal potential strategies for the enhancement of anti-PD-1/anti-CTLA-4 efficacy.
