Mechano-chemical regulation of the microenvironmental niche in melanoma

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Melanoma is an aggressive cancer with a high mortality rate once it metastasizes, with only 23% of patients surviving five years post-diagnosis. Despite various targeted therapies, patients frequently experience relapse and drug resistance. This underscores the urgent need for novel biomarkers to guide therapeutics, with tumor cell and tissue mechanical properties offering crucial insights into metastatic progression. While combinatorial immunotherapies, which harness the patient's immune system, have shown durable and curative responses, patient outcomes are heterogeneous, with some patients not responding or developing resistance. The tumor metabolic microenvironment (TMM) is recognized as a key regulator of therapy response, influencing the ability of infiltrating T cells to kill cancer cells, a vital factor in successful immunotherapy. Our research investigated organ-specific differences in tumor metabolism and immune infiltration in vivo, using 3D culture models, human cancer cell xenografts in mice, and larval zebrafish. We found these differences were linked to antigen presentation machinery, specifically Major Histocompatibility Complexes (MHCs), critical for immune cell activation against foreign entities like tumors. We observed variations in MR1 expression in tumors and T cells within metabolically distinct organ microenvironments, characterized by increased glycolysis versus oxidative phosphorylation. In immune-compromised environments (reduced T and B cells), tumors compensated by elevating MR1 levels in macrophages and Natural Killer cells compared to those with intact immune backgrounds. MR1, a highly conserved non-classical MHC-I complex, is a recently identified sensor that presents various metabolites to MR1-restricted T cells, aiding in bacterial infection detection. We confirmed organ-specific MR1 expression in freshly excised human metastatic melanomas, but not in normal adjacent tissue, and validated these findings using a genetic melanoma model. Recent evidence highlights a critical link between tumor mechanical properties and metabolic behavior. This motivated our studies using optical techniques in pre-clinical models to characterize the role of mechano-metabolism signatures in regulating T cell infiltration and signaling. This cycle, our focus is on metabolic shifts in T cells, antigen presentation mechanisms, and the unique mechanical properties of melanoma tumors. This research also earned an international award for its clinical promise. Key Findings: a) Role of Macrophages in MR1 Antigen Presentation in Melanoma: Our studies reveal the crucial role of macrophages in MR1 (Major Histocompatibility Complex-related protein 1) antigen presentation for melanomas. MR1-restricted T cells (MAIT cells) recognize microbial metabolites presented by MR1, contributing to immune surveillance. Our findings suggest that macrophages are key presenters of these antigens in melanomas, potentially influencing MAIT cell activation and function, and thus the overall anti-tumor immune response. Further research is needed to identify the specific MR1-presented ligands and their sources within melanoma. Moreover, it shows that understanding the adaptive response also requires that we understand organ specific behaviors of innate immune cells such as macrophages. b) T Cell Glycolysis in Melanoma: T cells infiltrating melanoma tumors exhibit, on average, an increased reliance on glycolysis compared to T cells in adjacent normal tissues. This metabolic reprogramming suggests adaptation to the nutrient-deprived and often hypoxic tumor microenvironment (TME), where glycolysis provides rapid ATP generation. This aligns with the understanding that immune cells undergo metabolic shifts to fuel diverse functions within the tumor context. c) Metabolic Heterogeneity of T Cells in Melanoma: Despite the overall trend towards glycolysis, our research uncovered significant metabolic heterogeneity among T cells within melanoma tumors. We observed a spectrum of metabolic states, from T cells primarily engaging in oxidative phosphorylation to those exhibiting a strong glycolytic phenotype. This heterogeneity underscores the diverse functional states and differentiation pathways T cells can adopt in response to varied TME signals. Understanding factors driving these distinct metabolic profiles could pave the way for targeted immunometabolic therapies. d) Organ-Specific Mechanical Properties of Tumors: Using our custom-built optical systems, we determined organ-specific mechanical properties of tumors within the same animal. This indicates that even with similar genetic backgrounds and tumor types, the surrounding tissue environment significantly influences the tumor's physical characteristics. These mechanical properties, such as stiffness and elasticity, are known to impact cell behavior (e.g., proliferation, migration, differentiation), drug delivery, and immune cell infiltration. This emphasizes the importance of considering the specific organ microenvironment in studying tumor progression and designing therapies. Our findings highlight the dynamic metabolic adaptations of T cells, the integral role of macrophages in MR1 antigen presentation, and the fascinating organ-specific mechanical properties of tumors. These discoveries collectively deepen our understanding of melanoma biology and offer promising avenues for novel therapeutic strategies, including metabolic modulation, targeted immunotherapy, and mechano-responsive interventions. Future research will focus on dissecting the underlying mechanisms driving these observations and translating these insights into preclinical and clinical applications to improve melanoma patient outcomes. Ultimately, our work aims to distinguish responders from non-responders and provide a mechanistic understanding of a patient's likely response to immunotherapies.