Browsing by Author "DeVito, Nicholas C"

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Open Access
Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.
(Journal of immunotherapy (Hagerstown, Md. : 1997), 2022-07) Oswalt, Cameron J; Al-Rohil, Rami N; Theivanthiran, Bala; Haykal, Tarek; Salama, April KS; DeVito, Nicholas C; Holtzhausen, Alisha; Ko, Dennis C; Hanks, Brent A
The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.
Open Access
Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.
(Cancers, 2021-09-23) Theivanthiran, Balamayooran; Haykal, Tarek; Cao, Linda; Holtzhausen, Alisha; Plebanek, Michael; DeVito, Nicholas C; Hanks, Brent A
The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.
Open Access
Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy.
(Cell reports, 2021-05) DeVito, Nicholas C; Sturdivant, Michael; Thievanthiran, Balamayooran; Xiao, Christine; Plebanek, Michael P; Salama, April KS; Beasley, Georgia M; Holtzhausen, Alisha; Novotny-Diermayr, Veronica; Strickler, John H; Hanks, Brent A
While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.
Open Access
Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.
(Frontiers in immunology, 2019-01) DeVito, Nicholas C; Plebanek, Michael P; Theivanthiran, Bala; Hanks, Brent A
The vast majority of cancer-related deaths are due to metastasis, a process that requires evasion of the host immune system. In addition, a significant percentage of cancer patients do not benefit from our current immunotherapy arsenal due to either primary or secondary immunotherapy resistance. Importantly, select subsets of dendritic cells (DCs) have been shown to be indispensable for generating responses to checkpoint inhibitor immunotherapy. These observations are consistent with the critical role of DCs in antigen cross-presentation and the generation of effective anti-tumor immunity. Therefore, the evolution of efficient tumor-extrinsic mechanisms to modulate DCs is expected to be a potent strategy to escape immunosurveillance and various immunotherapy strategies. Despite this critical role, little is known regarding the methods by which cancers subvert DC function. Herein, we focus on those select mechanisms utilized by developing cancers to co-opt and tolerize local DC populations. We discuss the reported mechanisms utilized by cancers to induce DC tolerization in the tumor microenvironment, describing various parallels between the evolution of these mechanisms and the process of mesenchymal transformation involved in tumorigenesis and metastasis, and we highlight strategies to reverse these mechanisms in order to enhance the efficacy of the currently available checkpoint inhibitor immunotherapies.