Immunity to X-linked inhibitor of apoptosis protein (XIAP) in malignant melanoma and check-point blockade

Jun Zhou; Jingjing Li; Indira Guleria; Tianqi Chen; Anita Giobbie-Hurder; Jonathan Stevens; Meghna Gupta; Xinqi Wu; Ryan C Brennick; Michael P Manos; F Stephen Hodi

doi:10.1007/s00262-019-02370-4

Immunity to X-linked inhibitor of apoptosis protein (XIAP) in malignant melanoma and check-point blockade

Cancer Immunol Immunother. 2019 Aug;68(8):1331-1340. doi: 10.1007/s00262-019-02370-4. Epub 2019 Jul 18.

Authors

Jun Zhou^{1

2

3}, Jingjing Li^{1

2

3}, Indira Guleria⁴, Tianqi Chen⁵, Anita Giobbie-Hurder^{3

5}, Jonathan Stevens⁴, Meghna Gupta^{1

2}, Xinqi Wu^{1

2}, Ryan C Brennick^{1

2

3}, Michael P Manos^{1

2

3}, F Stephen Hodi^{6

7

8

9}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
² Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³ Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴ Tissue Typing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. stephen_hodi@dfci.harvard.edu.
⁷ Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. stephen_hodi@dfci.harvard.edu.
⁸ Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. stephen_hodi@dfci.harvard.edu.
⁹ Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. stephen_hodi@dfci.harvard.edu.

Abstract

Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4⁺ T cell responses. XIAP epitope-specific CD4⁺ T cells revealed proliferative responses to melanoma cells that express XIAP. Humoral responses to XIAP were also explored. Cellular and humoral responses to XIAP were associated with beneficial clinical outcomes after ipilimumab-based treatment, supporting XIAP as a potential therapeutic target.

Keywords: CTLA4 blockade; Melanoma; PD-1 blockade; XIAP.

MeSH terms

Antineoplastic Agents / therapeutic use*
CD4-Positive T-Lymphocytes / immunology*
Cell Proliferation
Cells, Cultured
Enzyme-Linked Immunospot Assay
Epitopes, T-Lymphocyte / immunology*
Humans
Immunity, Humoral
Immunotherapy / methods*
Ipilimumab / therapeutic use*
Lymphocyte Activation
Melanoma / drug therapy
Melanoma / immunology*
Neoplasm Staging
Peptide Fragments / immunology*
Skin Neoplasms / drug therapy
Skin Neoplasms / immunology*
Treatment Outcome
X-Linked Inhibitor of Apoptosis Protein / immunology*

Substances

Antineoplastic Agents
Epitopes, T-Lymphocyte
Ipilimumab
Peptide Fragments
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human

Abstract

MeSH terms

Substances

Grants and funding