Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients.

Abstract

BACKGROUND:

Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response.

METHODS:

Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months.

RESULTS:

Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients.

CONCLUSIONS:

Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.

• Authors: Elena Crespo, Loreto Fernandez, Marc Lúcia, Edoardo Melilli, Ricardo Lauzurica, Rosa Maria Penin, Ariadna Quer, Sergio Luque, Maria Quero, Anna Manonelles, Joan Torras, Josep Maria Cruzado, Laura Cañas, Josep Maria Grinyó, Oriol Bestard
• Journal: Transplantation (Transplantation) Vol. 101 Issue 9 Pg. 2102-2110 (09 2017) ISSN: 1534-6080 [Electronic] United States
• PMID: 28403126 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antigens, Neoplasm
• Calcineurin Inhibitors
• Cytokines
• Immunosuppressive Agents
• Protein Kinase Inhibitors
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Aged
• Antigens, Neoplasm (immunology)
• Calcineurin Inhibitors (adverse effects)
• Carcinoma, Squamous Cell (chemically induced, immunology, metabolism, pathology)
• Case-Control Studies
• Cross-Sectional Studies
• Cytokines (immunology, metabolism)
• Drug Substitution
• Drug Therapy, Combination
• Female
• Humans
• Immunocompromised Host
• Immunosuppressive Agents (adverse effects)
• Kidney Transplantation (adverse effects)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Male
• Middle Aged
• Phenotype
• Protein Kinase Inhibitors (adverse effects)
• Skin Neoplasms (chemically induced, immunology, metabolism, pathology)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Treatment Outcome
• Tumor Escape (drug effects)