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Principal Investigator: Ashley Mello
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $41,664
Funding agency: National Cancer Institute
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy characterized by poor response to all existing
therapies. Although immunotherapy has shown great promise against multiple deadly cancers, single-agent
checkpoint immunotherapy has been largely ineffective in PDAC. This lack of response is in part attributed to its
extensive inflammatory, desmoplastic stromal reaction and hypoxic microenvironment. Although tumor hypoxia
induces adaptive changes in both cancer cells and the surrounding stroma, most studies on the role of hypoxia
in tumorigenesis have focused on cancer cell-intrinsic properties. The impact of hypoxia on stromal cells
themselves and their interactions with cancer cells has remained largely unknown. The major cell populations
found within the PDAC stroma—macrophages and fibroblasts—are known to be large producers of
immunosuppressive factors, some of which can negatively affect cytotoxic CD8+ T cell activity in tumors. CD8+
T cells play an essential role in the anti-tumor response and the efficacy of immunnotherapies relies on the
amount of CD8+ T cell infiltration within the tumor bed. Based on our preliminary observation that macrophages
and inflammatory fibroblasts are enriched in hypoxic tumor regions while T cells are excluded from hypoxic areas
in PDAC, I hypothesize that hypoxia suppresses infiltration and activation of CD8+ T cells by modulating their
interactions with macrophages and fibroblasts. In Specific Aim 1, I will determine whether macrophages are
critical for hypoxia-mediated CD8+ T cell exclusion and suppression by treating CD8+ T cells with conditioned
media derived from macrophage cultures under hypoxia and depleting macrophages in syngeneic orthotopic
PDAC tumors. In Specific Aim 2, I will determine how fibroblasts regulate CD8+ T cell recruitment and function
in hypoxic tumor regions by blocking a factor secreted from fibroblasts in syngeneic orthotopic PDAC tumors,
injecting a hypoxia probe into mice, and assessing CD8+ T cell infiltration and activation in hypoxic and normoxic
tumor regions. The results of my studies will further the field’s understanding of how hypoxia drives an
immunosuppressive microenvironment via the crosstalk between CD8+ T cells, macrophages, and fibroblasts,
and thus aid in the development of effective immunotherapeutic strategies.
Terms: <Affect><Antitumor Response><Area><Beds><Body Tissues><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CXCL9><CXCL9 gene><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Chemoattractants><Chemotactic Factors><Chemotaxins><Cholinergic Differentiation Factor><Clinical><D-Factor><Data><Data Set><Death><Desmoplastic><Desmoplastic Reaction><Development><Disease><Disorder><Exclusion><Exposure to><Fibroblasts><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Human><Humig><Hypoxia><Hypoxic><Hypoxic tumor><Immune Evasion><Immune mediated therapy><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><In Vitro><Infiltration><Inflammatory><LIF><LIF gene><LYT3><MIG Gene><Macrophage><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measures><Mediating><Mice><Mice Mammals><Modern Man><Murine><Mus><Mφ><Nutrient><O element><O2 element><Oncogenesis><Organoids><Oxygen><Oxygen Deficiency><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Play><Population><Proliferating><Property><Reaction><Regulation><Repression><Resistance><Role><SCYB9><Stromal Cells><Subcellular Process><Survival Rate><T cell infiltration><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Tissues><Tumor Cell><United States><Vascularization><activate T cells><anti-tumor response><cancer cell><cancer microenvironment><cancer progression><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><complement chemotactic factor><crg-10><cytokine><cytotoxic><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><design><designing><developmental><exhaustion><experience><glioblastoma multiforme><immune check point therapy><immune checkpoint therapy><immune drugs><immune evasive><immune microenvironment><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic therapeutics><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><insight><leukemia inhibitor factor><leukemia inhibitory factor><malignancy><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neutralizing antibody><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><normoxia><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pancreatic cancer cells><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><patient oriented outcomes><prevent><preventing><recruit><resistant><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spongioblastoma multiforme><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><tumor><tumor hypoxia><tumor immune microenvironment><tumor microenvironment><tumor progression><tumor-immune system interactions><tumorigenesis>