KGCRF Poster Competition Winners 2024

KGCRF Rising Young Scientist Award – up to & including G3s

CAMERON FRASER | G1
Biological Sciences in Public Health
Jessalyn Ubellacker Lab

Sublethal lipid peroxidation in cancer cells in lymph nodes triggers systemic anti-cancer immunity
Cancer progression requires evading immune system responses, and T cell activation plays a critical role in initiating an adaptive immune response for widespread anti-tumor clearance. While there is existing evidence that inhibition of the crucial reducing enzyme glutathione peroxidase 4 (Gpx4) in cancer cells can lead to the secretion of damage-associated molecular patterns (DAMPs), there is limited understanding of the extent to which lipid peroxidation in cancer cells can mediate an adaptive immune response. The abundance of antigen-presenting cells and immune cell populations in the lymph node comprise an ideal microenvironment for dendritic cell/T cell cross-presentation and activation in the context of anti-cancer immunogenicity. Here, we demonstrate that inducing lipid peroxidation in lymph node cancer cells enhances systemic anti-cancer immunity by promoting antigen cross-presentation and T cell activation. Using murine breast and melanoma models with Gpx4 deletion, Gpx4-/- tumors grow comparably when engrafted into lymph nodes. We establish an ex vivo system to assess immune activity and show that CD8+ T cells from Gpx4-/- lymph node tumors exhibit enhanced cytotoxicity ex vivo compared to WT. Co-culturing CD8+ T cells with CD11c+ dendritic cells further enhances cytotoxicity. These findings suggest a novel mechanism for provoking systemic anti-cancer adaptive immunity—by inhibiting Gpx4 locally in melanoma and breast cancer cells within lymph nodes, thus triggering DAMP and cytokine production to initiate immune-mediated tumor clearance both locally in the lymph nodes, and systemically at distant metastatic sites.

ALAN WONG | G3
Biological and Biomedical Sciences
Naama Kanarek Lab

In vivo CRISPR screen identifies copper metabolism as a vulnerability in ALL
Acute Lymphoblastic Leukemia (ALL) is one of the most common childhood cancers and remains a significant cause of pediatric cancer mortality in the USA. Prophylactic chemotherapy delivered to the central nervous system (CNS) is a critical part of treatment because leukemia that spreads to the CNS is often fatal. However, CNS-directed chemotherapy is associated with serious side effects including long-term cognitive disability. Our goal is to identify cancer-specific vulnerabilities of leukemia cells in the CNS that can serve as therapeutic targets.

A unique but understudied aspect of leukemia in the CNS is that cancer cells are moving from the blood to a new and quite distinct metabolic environment: the cerebrospinal fluid. We hypothesize that adapting to this new metabolic environment creates unique and targetable weaknesses in spreading leukemia cells. To address this hypothesis, we conducted a targeted 172-gene in vivo metabolic CRISPR knockout screen in a xenograft murine model of acute lymphoblastic leukemia. Our screen revealed genes involved in copper metabolism and oxidative phosphorylation as in vivo dependencies in ALL. Knockout of the cell-surface copper importer SLC31A1 significantly reduces ALL growth in vivo in the periphery as well as in the cerebrospinal fluid. In vitro, perturbation of copper metabolism by SLC31A1 knockout leads to an isolated complex IV deficiency and reduced oxygen consumption, ultimately slowing cell proliferation. Cell proliferation in knockout cells is rescued by genetic restoration of the electron transport chain (ETC), or by providing exogenous nucleotide precursors, functionally linking copper import, ETC activity and nucleotide synthesis. Our ongoing work seeks to validate the efficacy of copper chelation in cell-line based and patient-derived xenograft models of ALL, as well as to evaluate the copper status of leukemia cells in vivo.

KGCRF Early Career Investigator Award – G4s & up

MONICA CASSANDRAS | G4
Biological and Biomedical Sciences
Judith Agudo Lab

Chronic stress promotes immune evasion in breast cancer metastasis
Metastasis occurs when disseminated tumor cells (DTCs) escape killing by surveilling cytotoxic immune cells. The mechanisms of DTC immune evasion are currently not well understood, and this represents a crucial barrier to developing effective therapies. We investigate this by utilizing our novel JEDI mouse, in which cytotoxic T cells target tumor cells for killing. By profiling the DTCs that successfully survive JEDI immune attack, we unexpectedly discovered that chronic stress hormone (glucocorticoid) signaling is a top driver of immune evasion in lung metastasis. This suggests that activation of the glucocorticoid receptor (GR) promotes an immune evasive state in DTCs. Indeed, patients with advanced breast cancer have higher levels of glucocorticoids, and elevated GR activity correlates with worse survival. Consistently, we found that mice with metastasis have significantly higher levels of circulating glucocorticoids. We determined that GR signaling in DTCs directly blocks cytotoxic lymphocyte killing to increase metastatic survival. Mechanistically, DTCs harness stress hormones to repress the death receptor FAS and acquire an overall anti-apoptotic phenotype. Exploiting the mechanisms by which tumor-intrinsic GR signaling prevents killing by cytotoxic immune cells represents promising new avenues for preventing metastasis and opens the door for new combinatorial treatments with current immunotherapy regimens.

PETER GEORGIEV | G4
Immunology
Arlene Sharpe & Marcia Haigis Labs

Age-associated contraction of tumor-specific T cells impairs anti-tumor immunity
Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in anti-tumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We find that multiple syngeneic cancers grow more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T cell responses. By systematically mapping immune cell profiles within tumors, we identify loss of tumor antigen-specific CD8+ T cells as a primary feature accelerating the growth of tumors in aged mice and driving resistance to immunotherapy. Administration of young antigen-specific T cells to aged mice delays tumor outgrowth and is sufficient to sensitize aged animals to PD-1 blockade. These studies reveal how age-associated CD8+ T cell dysfunction may license tumorigenesis in elderly patients and have important implications for the use of aged mice as pre-clinical models of aging and cancer.