Biomedical subjects

Hadiya K Giwa

Publications and source records attributed to Hadiya K Giwa.

2 recordsLinked to original sources

PubMed2025

MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T-cell and Immunotherapy Responses in Prostate Cancer.

UNLABELLED: Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor-targeted treatments and immunotherapies. Genetic alterations acquired during the evolution of CRPC may affect antitumor immunity and immunotherapy responses, which could inform personalized therapeutic strategies. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor-intrinsic secretion of VEGF, which signaled through VEGFR2 expressed on CD8+ T cells to directly inhibit T-cell migration and effector functions. Targeting VEGF-VEGFR2 signaling in vivo remodeled the immunosuppressive prostate tumor microenvironment, leading to CD8+ T-cell-mediated primary tumor and metastasis growth suppression and significantly increased overall survival in MYC- and p53-altered CRPC. VEGFR2 blockade also led to the induction of PD-L1 in tumors and produced antitumor efficacy in combination with PD-L1 immune checkpoint blockade in multiple preclinical CRPC mouse models. Thus, these results identify a genetic mechanism of immunosuppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC. SIGNIFICANCE: VEGFR2 blockade inhibits VEGF-mediated T-cell suppression and potentiates the effects of PD-L1 immune checkpoint blockade to treat castration-resistant prostate cancer driven by MYC and p53 alterations.

Male↗

PubMed2025

PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors.

Immunotherapy modalities have revolutionized cancer treatment for a number of metastatic and treatment-refractory tumor types. Still, many malignancies that lack T cell infiltration and are termed immunologically "cold" fail to respond to these modalities. One approach to increase tumor immunogenicity has been to induce stimulator of interferon gene (STING) and downstream interferon signaling that is often dysregulated in cold tumors. Despite some early success of STING agonists in preclinical cancer models, these approaches have not been successful in the clinic due to poor tumor penetrance and systemic toxicities. Here, we performed a genome-wide CRISPR screen to uncover therapeutic targets to activate STING expression in human tumors. We identified the lysosomal hydrolase Palmitoyl Protein Thioesterase1 (PPT1) as a negative regulator of STING highly expressed in cold ovarian and prostate tumors. Genetic or pharmacological PPT1 suppression increased STING protein stability and its downstream activation of interferon and inflammatory cytokine signaling to enhance T cell migration. Treatment of preclinical prostate and ovarian cancer models expressing low levels of STING with the small molecule PPT1 inhibitor GNS561 enhanced STING expression and activation, leading to infiltration and activation of cytotoxic T cells that turned these tumors "hot" and reduced tumor growth, fibrosis, and dissemination without toxicity. Further analysis demonstrated that PPT1 is associated with reduced STING expression, CD8+ T cell numbers, overall survival, and immunotherapy outcomes in ovarian and prostate cancer patients. Thus, PPT1 inhibition may be a promising approach to activate STING and potentiate the effects of immunotherapy in cold tumors.

Membrane Proteins↗