Merkel cell carcinoma (MCC) is an often-lethal skin cancer with a reported incidence that has quadrupled in the past 20 years to ~1,600 cases/year in the US. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered to be integrated in ~80% of MCC tumors. MCCs require persistent expression of the viral T antigen (T-Ag) oncoprotein for growth, providing a target for rational immune therapy. Although most MCC patients have no apparent immune defect, persons with T cell dysfunction due to HIV, chronic leukemia or immunosuppressive drugs have a 10- to 30-fold increased MCC risk. This proposal builds on our findings that humoral immune responses to T-Ag are linked to MCC progression while cellular immune responses appear to be protective. Similar to the other known human polyomaviruses, MCPyV infection is prevalent in the general population (53% of adults have anti-MCPyV capsid protein antibodies). In marked contrast, we have found that antibodies to MCPyV T-Ag oncoproteins are rare in population controls (1%) but are prevalent among newly diagnosed MCC patients (~50%). Moreover, anti-T-Ag antibody titers are dynamic in MCC patients and increase in parallel to tumor burden, allowing detection of disease progression in some cases before identification by the patient or physician.
In Aim 1, we propose to further characterize anti-T-Ag antibodies and to test their clinical utility as a specific biomarker for MCC recurrence. We have also found that cell-mediated immunity (intratumoral CD8+ T cell infiltration) is associated with excellent MCC prognosis. Therefore, in collaboration with Dr. David Koelle, in Aim 2 we will comprehensively map T cell epitopes/MHC restriction for MCPyV oncoproteins, develop peptide-MHC reagents, and use them to characterize the frequency and function of MCPyV-specific T cells in the blood and tumors of MCC patients.
In Aim 3, we will use human tumor samples and a mouse model of MCC to determine the potential efficacy of three immune stimulating therapies for possible future human MCC trials. These studies will be performed in close collaboration with Drs. Thomas Blankenstein and Gerald Willimsky using their existing, well-characterized mouse model of spontaneous polyomavirus-induced cancer that shares striking biologic, clinical, and immunologic similarities with MCC. This proposal combines the expertise of investigators who each have over ten years of documented productivity in three synergistic areas: clinical and translational research in MCC (Nghiem), comprehensive characterization of the cellular immune response to human skin-associated viruses (Koelle) and characterization of the humoral and cellular immune responses to polyomavirus-driven sporadic cancer in mouse models (Blankenstein/Willimsky). Because antigen-specific cellular and humoral responses to viral proteins expressed in MCC can be tracked, these studies will provide significant biological insight into the immune response to cancer more generally, with directly applicable prognostic and therapeutic implications for MCC patients.

Public Health Relevance

Merkel cell carcinoma (MCC) is an aggressive skin cancer that is typically caused in part by a recently discovered human polyomavirus. This proposal builds on our findings in patients that antibodies against this polyomavirus may be associated with MCC progression while killer T cell responses are linked to improved survival. We believe the proposed studies will provide insight into the immune response to cancer more generally, establish a clinically important blood test for MCC disease status, as well as lay critical groundwork for future immune therapy clinical trials in this often-lethal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA162522-04
Application #
8699706
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Thurin, Magdalena
Project Start
2011-09-16
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$319,784
Indirect Cost
$116,531
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Lyngaa, Rikke; Pedersen, Natasja Wulff; Schrama, David et al. (2014) T-cell responses to oncogenic merkel cell polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors. Clin Cancer Res 20:1768-78
Paulson, Kelly G; Tegeder, Andrew; Willmes, Christoph et al. (2014) Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma. Cancer Immunol Res 2:1071-9
Blom, Astrid; Bhatia, Shailender; Pietromonaco, Stephanie et al. (2014) Clinical utility of a circulating tumor cell assay in Merkel cell carcinoma. J Am Acad Dermatol 70:449-55
Iyer, Jayasri G; Storer, Barry E; Paulson, Kelly G et al. (2014) Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 70:637-43
Moshiri, Ata S; Nghiem, Paul (2014) Milestones in the staging, classification, and biology of Merkel cell carcinoma. J Natl Compr Canc Netw 12:1255-62
Asgari, Maryam M; Sokil, Monica M; Warton, E Margaret et al. (2014) Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma. JAMA Dermatol 150:716-23
Miller, Natalie J; Bhatia, Shailender; Parvathaneni, Upendra et al. (2013) Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma. Curr Treat Options Oncol 14:249-63
Afanasiev, Olga K; Yelistratova, Lola; Miller, Natalie et al. (2013) Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res 19:5351-60
Paulson, Kelly G; Iyer, Jayasri G; Byrd, David R et al. (2013) Pathologic nodal evaluation is increasingly commonly performed for patients with Merkel cell carcinoma. J Am Acad Dermatol 69:653-4

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