Nicholas DeVito

Overview:

I am an instructor of Medical Oncology who primarily treats patients with gastrointestinal malignancies. My laboratory and translational research is focused on tumor immune evasion and immunotherapy, with a specific interest in dendritic cell tolerance.

Positions:

Medical Instructor in the Department of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2012

University of South Florida, College of Medicine

Internal Medicine Internship and Residency

Tufts University School of Medicine

Hematology-Oncology Fellowship, Medicine

Duke University School of Medicine

Grants:

Publications:

Role of dendritic cell metabolic reprogramming in tumor immune evasion.

The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.
Authors
Plebanek, MP; Sturdivant, M; DeVito, NC; Hanks, BA
MLA Citation
Plebanek, Michael P., et al. “Role of dendritic cell metabolic reprogramming in tumor immune evasion.Int Immunol, vol. 32, no. 7, June 2020, pp. 485–91. Pubmed, doi:10.1093/intimm/dxaa036.
URI
https://scholars.duke.edu/individual/pub1442098
PMID
32449776
Source
pubmed
Published In
Int Immunol
Volume
32
Published Date
Start Page
485
End Page
491
DOI
10.1093/intimm/dxaa036

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Authors
Theivanthiran, B; Evans, KS; DeVito, NC; Plebanek, M; Sturdivant, M; Wachsmuth, LP; Salama, AK; Kang, Y; Hsu, D; Balko, JM; Johnson, DB; Starr, M; Nixon, AB; Holtzhausen, A; Hanks, BA
MLA Citation
Theivanthiran, Balamayoora, et al. “A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.J Clin Invest, vol. 130, no. 5, May 2020, pp. 2570–86. Pubmed, doi:10.1172/JCI133055.
URI
https://scholars.duke.edu/individual/pub1431106
PMID
32017708
Source
pubmed
Published In
J Clin Invest
Volume
130
Published Date
Start Page
2570
End Page
2586
DOI
10.1172/JCI133055

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.

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.
Authors
DeVito, NC; Plebanek, MP; Theivanthiran, B; Hanks, BA
MLA Citation
DeVito, Nicholas C., et al. “Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.Front Immunol, vol. 10, 2019, p. 2876. Pubmed, doi:10.3389/fimmu.2019.02876.
URI
https://scholars.duke.edu/individual/pub1426782
PMID
31921140
Source
pubmed
Published In
Frontiers in Immunology
Volume
10
Published Date
Start Page
2876
DOI
10.3389/fimmu.2019.02876

A tumor PD-L1-NLRP3 inflammasome signaling axis drives adaptive resistance to anti-PD-1 immunotherapy

Authors
Theivanthiran, B; Evans, K; DeVito, N; Plebanek, M; Sturdivant, M; Holtzhausen, A; Wachsmuth, L; Salama, A; Kang, Y; Hsu, D; Balko, J; Johnson, D; Starr, M; Nixon, A; Hanks, B
MLA Citation
Theivanthiran, Balamayooran, et al. “A tumor PD-L1-NLRP3 inflammasome signaling axis drives adaptive resistance to anti-PD-1 immunotherapy.” Journal for Immunotherapy of Cancer, vol. 7, BMC, 2019.
URI
https://scholars.duke.edu/individual/pub1422606
Source
wos
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date

Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.

Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAFV600E melanoma. Additional mechanistic studies revealed that TGFβ pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGFβ signaling activity. Delayed TGFβ inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGFβ inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGFβ inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance.See related Spotlight on p. 1444.
Authors
Zhao, F; Evans, K; Xiao, C; DeVito, N; Theivanthiran, B; Holtzhausen, A; Siska, PJ; Blobe, GC; Hanks, BA
MLA Citation
Zhao, Fei, et al. “Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.Cancer Immunol Res, vol. 6, no. 12, Dec. 2018, pp. 1459–71. Pubmed, doi:10.1158/2326-6066.CIR-18-0086.
URI
https://scholars.duke.edu/individual/pub1349797
PMID
30209062
Source
pubmed
Published In
Cancer Immunol Res
Volume
6
Published Date
Start Page
1459
End Page
1471
DOI
10.1158/2326-6066.CIR-18-0086