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Open Access Publications from the University of California

Scholarly Works (22 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2023)

Macrophages are innate immune cells that play key roles in infection, immunity and cancer. Understanding the mechanisms that control macrophage contributions to cancer can help to develop strategies to improve cancer therapy. Oncogenic mutations allow cancer cells to take up nutrients through a process called macropinocytosis or “cell-drinking”, which promotes cancer cell survival and proliferation. The role of macropinocytosis has been studied in various cancers but has been less well explored in macrophages. Macropinocytosis in macrophages may help these cells to survive in the harsh tumor microenvironment. Thus, one of the goals of this project is to investigate macrophage macropinocytosis by studying the uptake of Tetramethyl rhodamine (TMR-dextran) in macrophages. My hypothesis is that PI3Kgamma plays a role in promoting macropinocytosis in macrophages. Through macropinocytosis assays using TMR-dextran, we found that PI3Kgamma inhibition successfully suppressed macropinocytosis in iWT macrophages. To further study macrophages, we tested the effect of 3G8, a small molecular drug that inhibits FLT3, CKIT and CSF1R, on mitochondrial function. We had found that 3G8 can also stimulates release of mitochondrial ROS. My hypothesis is that 3G8 activates the mitochondrial permeability transition pore (thereby releasing ROS and impacting cell signaling). Through mitochondrial permeability transition pore activity (mPTP) assays, we observed that 3G8 induced opening of the mPTP in macrophages and tumor cells. Understanding the mechanisms by which these inhibitors function in macrophages could help with the development of anti-cancer therapeutics and thus reduce the effects of cancer.

    Cover page: An Analysis of Novel Macrophage Targeted Therapeutics That Impact Macropinocytosis and Mitochondrial Permeability
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2012)
    Abstract Bone marrow derived myeloid cells progressively accumulate in tumors, where they establish an inflammatory microenvironment that is favorable for tumor growth and spread. These cells are comprised primarily of monocytic and granulocytic myeloid derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs), which are generally associated with a poor clinical outcome. MDSCs and TAMs promote tumor progression by stimulating immunosuppression, neovascularization, metastasis and resistance to anti-cancer therapy. Strategies to target the tumor-promoting functions of myeloid cells could provide substantial therapeutic benefit to cancer patients.
      Cover page: Myeloid cells in tumor inflammation
      • Thesis
      • Peer Reviewed
      UC San Diego Electronic Theses and Dissertations (2023)

      Tumor-associated macrophages (TAMs) create an immunosuppressive tumor microenvironment (TME) that will promote tumor progression. The goal of this project is to understand whether the pattern of TAMs in a tumor is determined by the tumor cells or by the host tissue environment. Knowing how the phenotype of TAMs is determined will help us better target TAMs to improve cancer patient’s outcome. Moreover, another goal of this project is to understand whether the TAMs that develop in a primary tumor have the same phenotype as those that develop in subsequent metastases. Comparing gene expression profiles between TAMs in different tissues can provide future directions to improve cancer therapies so that we can better target TAMs in order to effectively eradicate primary and metastatic tumors.

      Using flow cytometry to examine like tumors growing in different tissues, we found that subcutaneous, orthotopic, and intravenous LLC tumor models all have similar TAM profiles that are distinct from genetically engineered CC10Cre KrasG12D p53-/- spontaneous lung tumor models. In addition, using single-cell sequencing to investigate the PyMT primary mammary gland tumors and metastatic lung tumor the and CC10Cre KrasG12D p53-/- spontaneous lung tumors, we can conclude that the TAM profile of the primary tumor and subsequent metastasized tumor have similar TAM profiles. As a result, we can conclude that the TAM profile is dependent on the tumor cells themselves instead of the microenvironment.

        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2017)
        Immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) accumulate in tumors where they inhibit T cell-mediated antitumor immune responses and promote tumor progression. Myeloid cell PI3Kγ plays a role in regulating tumor immune suppression by promoting integrin α4-dependent MDSC recruitment to tumors and by stimulating the immunosuppressive polarization of MDSCs and TAMs. Here, we show that integrin α4 promotes immunosuppressive polarization of MDSCs and TAMs downstream of PI3Kγ, thereby inhibiting antitumor immunity. Genetic or pharmacological suppression of either PI3Kγ or integrin α4 blocked MDSC recruitment to tumors and also inhibited immune suppressive myeloid cell polarization, thereby reducing expression of IL10 and increasing expression of IL12 and IFNγ within tumors. Inhibition of PI3Kγ or integrin α4 within tumors stimulated dendritic cell and CD8+ T-cell recruitment and maturation, as well as tumor cell cytotoxicity in vivo, thereby inhibiting tumor growth. As blockade of PI3Kγ or integrin α4 prevents accumulation of MDSC and reduces myeloid cell expression of immunosuppressive factors that stimulate tumor immune escape, these results highlight PI3Kγ and integrin α4 as targets for the design of cancer therapeutics. Cancer Immunol Res; 5(11); 957-68. ©2017 AACR.
          Cover page: PI3Kgamma activates integrin alpha4 and promotes immune suppressive myeloid cell polarization during tumor progression
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2019)
          Despite the promise of ribonucleic acid interference therapeutics, the delivery of oligonucleotides selectively to diseased tissues in the body, and specifically to the cellular location in the tissues needed to provide optimal therapeutic outcome, remains a significant challenge. Here, key material properties and biological mechanisms for delivery of short interfering RNAs (siRNAs) to effectively silence target-specific cells in vivo are identified. Using porous silicon nanoparticles as the siRNA host, tumor-targeting peptides for selective tissue homing, and fusogenic lipid coatings to induce fusion with the plasma membrane, it is shown that the uptake mechanism can be engineered to be independent of common receptor-mediated endocytosis pathways. Two examples of the potential broad clinical applicability of this concept in a mouse xenograft model of ovarian cancer peritoneal carcinomatosis are provided: silencing the Rev3l subunit of polymerase Pol ζ to impair DNA repair in combination with cisplatin; and reprogramming tumor-associated macrophages into a proinflammatory state.
            Cover page: Securing the Payload, Finding the Cell, and Avoiding the Endosome: Peptide‐Targeted, Fusogenic Porous Silicon Nanoparticles for Delivery of siRNA
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2025)
            Background: Phosphoinositide 3-kinase is a potent target for cancer therapy due to its significant role in the regulation of cellular growth and proliferation. Dysregulation of the PI3k signaling cascade can constitutively activate growth pathways to trigger the progression of cancer, resulting in the development of multiple inhibitors as cancer therapeutics. Objectives: The wide array of cells expressing PI3k also include immune cells, and the inhibition of these receptors has shown promise in combating inflammation and infectious disease, a relationship we sought to examine further. Methods: We infected wild-type and PI3kγ knockout murine macrophages as well as PI3kγ inhibitor-treated THP-1 human macrophage-like cells with Staphylococcus aureus and quantified inflammation through gene expression analysis, protein secretion assays, and immunofluorescence imaging. Results: We observed that knockout of PI3kγ in murine macrophages alongside pharmacological inhibition through IPI549 treatment in THP-1 cells led to an NF-κB-driven suppression in transcription and release of inflammatory cytokines upon infection with methicillin-resistant Staphylococcus aureus. We were also able to confirm that this suppression of NF-κB translocation and subsequent decrease in inflammatory cytokine release did not compromise and even slightly boosted the bacterial killing ability. Conclusion: PI3k is primarily targeted for cancer therapies, but further exploration can also be carried out on its potential roles in treating bacterial infection.
              Cover page: The Role of PI3k-Gamma Modulation in Bacterial Infection: A Review of the Literature and Selected Experimental Observations
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2019)
              Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the coenrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 "don't eat me" signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers. SIGNIFICANCE: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvβ3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.
                Cover page: Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2022)
                Myeloid cells play key roles in cancer immune suppression and tumor progression. In response to tumor derived factors, circulating monocytes and granulocytes extravasate into the tumor parenchyma where they stimulate angiogenesis, immune suppression and tumor progression. Chemokines, cytokines and interleukins stimulate PI3Kγ-mediated Rap1 activation, leading to conformational changes in integrin α4β1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kγ activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin α4β1 activation. Genetic or pharmacological inhibition of MLCK210 suppresses integrin α4β1 activation, as well as tumor inflammation and progression. These results demonstrate a critical role for myeloid cell MLCK210 in tumor inflammation and serve as basis for the development of alternative approaches to develop immune oncology therapeutics.
                  Cover page: PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammationCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2015)
                  High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.
                    Cover page: Integrin α4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCNlow Neuroblastoma
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2024)
                    Viruses can be designed to be tools and carrier vehicles for intratumoural immunotherapy. Their nanometre-scale size and shape allow for functionalization with or encapsulation of medical cargoes and tissue-specific ligands. Importantly, immunotherapies may particularly benefit from the inherent immunomodulatory properties of viruses. For example, mammalian viruses have already been tested for oncolytic virotherapy, and bacteriophages and plant viruses can be engineered for immunotherapeutic treatment approaches. In this Review, we discuss how viruses - including oncolytic viruses, immunomodulatory plant viruses and bacteriophages - and virus-like particles can be designed for intratumoural immunotherapy to elicit anti-tumour immunity and induce systemic anti-tumour responses at distant non-injected sites. We further highlight the engineering of viruses and virus-like particles as drug-delivery systems, and outline key translational challenges and clinical opportunities.
                      Cover page: Virus nanotechnology for intratumoural immunotherapy.
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