Deciphering Brain Stroma-Regulated Immune Microenvironment in Melanoma Brain Metastasis
Abstract
The brain is one of the common organs for melanoma recurrence. Compared to carcinoma, melanoma has a much higher propensity to metastasize to the brain: over one-third of metastatic melanoma patients develop a clinically apparent brain metastasis. Patients with brain metastasis suffer from neurological deterioration, diminished quality of life, and only 4-12 months survival time even with aggressive treatments. For the past decade, immunotherapy has shown significant therapeutic efficacy for the treatment of melanoma, especially metastatic melanoma. Patients with active brain metastatic lesions were invariably excluded from the earlier immunotherapy clinical trials. However, retrospective studies indicate that immunotherapies improved overall survival in brain metastasis patients. Recent clinical trials have focused on the immune checkpoint blockage in brain metastasis lesions and shown promising results. Even though these clinical data indicate that immune responses regulate brain metastatic outgrowth, little is known about the immune microenvironment in the brain metastatic lesions. Metastasis is the consequence of favorable interactions between the invaded cancer cells and the microenvironment in the distal organ. Upon arrival in the distal organs, adaptation of cancer cells in the new microenvironment is the most stringent rate-limiting step in establishing metastasis. Similar to cancer cells, circulating immune cells also recruit into the distal organs and are modified by the surrounding cells. To cancer cells and immune cells, the brain has the most unique microenvironment since the brain stromal cells do not exist in any other organs. Thus, the objective of our proposal is to fill critical knowledge gaps by exploring how the brain stromal cells regulate the infiltrated immune cells in melanoma brain metastasis. The proposed work addresses the fiscal year 2022 Melanoma Research Program Focus Area: identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impacts tumor initiation, response to therapy, progression, recurrence, and/or dormancy. Astrocytes are the most abundant cells in the brain. Moreover, astrocytes get activated by the invading metastatic cancer cells and contribute to brain metastasis. Thus, we hypothesize that activated astrocytes create a unique immune microenvironment in melanoma brain metastasis. We will address the following questions: Aim 1. Many immunotherapies, including immune checkpoint inhibition, are based on activating cancer killing T lymphocytes. However, there are fewer lymphocytes in brain metastatic lesions. Here, we aim to study whether the metastasis-activated astrocytes regulate the vascular endothelial cells to limit the recruitment of the circulating T lymphocytes into the brain. The results will help us to identity new therapeutic strategies to overcome this issue by increasing lymphocytes in the brain metastatic lesions and consequentially improve the therapeutic efficacy of the current immunotherapies. Aim 2. Unlike the low level of lymphocyte infiltration, monocytic myeloid cells maintain the ability to get into brain metastatic lesions. Unfortunately, these monocytic myeloid cells are immunosuppressive to facilitate the metastatic outgrowth. Thus, we aim to understand how the metastasis-activated astrocytes help: (i) the myeloid cell infiltration, and (ii) facilitate the immunosuppressive function of monocytic myeloid cells. The goal is to identify new therapeutic strategies to overcome the immunosuppressive microenvironment created by monocytic myeloid cells in brain metastasis. Overall, our idea is that once we know how the astrocytes regulate the immune microenvironment to help cancer growth in the brain, we can focus our efforts on stopping it. Our research proposal will yield real and actionable targets on the brain microenvironment, instead of on cancer cells, to treat brain metastasis. Identifying strategies t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311050
Entities
People
- Qing Chen
Organizations
- United States Army
- Wistar Institute