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CTLA4 blockade broadens the peripheral T-cell receptor repertoire.


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

SUBMITTER: Robert L 

PROVIDER: S-EPMC4008652 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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CTLA4 blockade broadens the peripheral T-cell receptor repertoire.

Robert Lidia L   Tsoi Jennifer J   Wang Xiaoyan X   Emerson Ryan R   Homet Blanca B   Chodon Thinle T   Mok Stephen S   Huang Rong Rong RR   Cochran Alistair J AJ   Comin-Anduix Begoña B   Koya Richard C RC   Graeber Thomas G TG   Robins Harlan H   Ribas Antoni A  

Clinical cancer research : an official journal of the American Association for Cancer Research 20140228 9


<h4>Purpose</h4>To evaluate the immunomodulatory effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).<h4>Experimental design</h4>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.<h4>Results</h4>After receiving tremelimumab, t  ...[more]

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