Biology subjects

Watson, D. C.

Publications and source records attributed to Watson, D. C..

6 recordsLinked to original sources

bioRxiv2026

Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity

Metabolic dysfunction is a hallmark of CD8+ T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8+ T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8+ T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8+ T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8+ T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8+ T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8+ T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8+ T cell responses.

immunology↗

bioRxiv2024

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter {gamma}-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

cancer biology↗

bioRxiv2022

Sex-specific T cell exhaustion drives differential immune responses in glioblastoma

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunological sex differences are not fully understood. Using GBM models, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased T cell infiltration and increased T cell exhaustion. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD1 treatment. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, which was further corroborated by in vitro exhaustion assays. Moreover, increased T cell exhaustion was observed in male GBM patients. These findings demonstrate sex-specific pre-determined behavior of T cells is critical in inducing sex differences in GBM progression and immunotherapy response. Statement of significanceImmunotherapies in GBM patients have been unsuccessful due to a variety of factors including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-specific T cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve therapeutic efficacy of immunotherapy in GBM.

immunology↗

bioRxiv2021

SerpinB3 drives cancer stem cell survival in glioblastoma

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC therapeutic resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. The knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. Mechanistically, SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown dramatically increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of standard-of-care GBM therapies against therapeutically resistant CSCs. SummaryLauko et al. demonstrate a functional role for SerpinB3, which is elevated in glioblastoma cancer stem cells and protects against lysosomal-mediated cell death. SerpinB3 can be targeted to increase the efficacy of radiation in glioblastoma pre-clinical models.

cancer biology↗

bioRxiv2021

Horizontal mitochondrial transfer from the microenvironment increases glioblastoma tumorigenicity

While dynamic microenvironmental interactions drive tumor growth and therapeutic resistance, the underlying direct cell-cell communication mechanisms remain poorly understood. We identified horizontal mitochondrial transfer as a mechanism that enhances tumorigenesis in glioblastoma. This transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth. One-Sentence SummaryMitochondrial transfer from astrocytes to glioblastoma alters metabolic profile and enhances the tumor-initiation capacity.

cancer biology↗

bioRxiv2020

Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

Myeloid-derived suppressor cells (MDSCs) that block anti-tumor immunity are elevated in glioblastoma (GBM) patients. However, the distinct contribution of monocytic (mMDSC) versus granulocytic (gMDSC) subsets has yet to be determined. We observed that mMDSCs were enriched in the male tumor microenvironment, while gMDSCs were elevated in the circulation of female GBM models. Depletion of peripheral gMDSCs extended the survival only in female mice. Using gene expression signatures coupled with network medicine analysis, we demonstrated in pre-clinical models that mMDSCs could be targeted with anti-proliferative agents in males, whereas gMDSC function in females could be inhibited by IL-1{beta} blockade. Analysis of patient data confirmed that proliferating mMDSCs were the predominant population in male tumors, and that a high gMDSC/IL-1{beta} gene signature correlated with poor prognosis of female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. Statement of SignificanceSexual dimorphism at the level of MDSC subset prevalence, localization and gene expression profile comprises a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSC in males, while IL-1 pathway inhibitors can provide benefit to females through blockade of gMDSC function.

immunology↗