CTLA4 blockade broadens the peripheral T-cell receptor repertoire

Lidia Robert ¹, Jennifer Tsoi , Xiaoyan Wang , Ryan Emerson , Blanca Homet , Thinle Chodon , Stephen Mok , Rong Rong Huang , Alistair J Cochran , Begoña Comin-Anduix , Richard C Koya , Thomas G Graeber , Harlan Robins , Antoni Ribas

Affiliations

¹ Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine, Departments of Molecular and Medical Pharmacology, Medicine Statistics core, and Pathology and Laboratory Medicine, Division of Surgical-Oncology, Department of Surgery, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; Fred Hutchinson Cancer Research Center; Adaptive Biotechnologies, Seattle, Washington; and Instituto de Salud Carlos III, Madrid, Spain.

PMID: 24583799
40 References
168 citations

Abstract

Purpose: To evaluate the immunomodulatory effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).

Experimental Design: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab.

Results: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders.

Conclusions: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system.

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