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. 2014 May 1;20(9):2424-32.
doi: 10.1158/1078-0432.CCR-13-2648. Epub 2014 Feb 28.

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

CTLA4 blockade broadens the peripheral T-cell receptor repertoire

Lidia Robert et al. Clin Cancer Res. .

Erratum in

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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Conflict of interest statement

The rest of the co-authors have no conflict of interest.

Figures

Figure 1
Figure 1. Change in absolute number of unique productive sequences
A.) Changes reported between baseline and post-tremelimumab samples from 21 patients with melanoma (GA, in black) and from four healthy donors (HD, in grey). B) Normalized TCR V-beta CDR3 repertoire diversity. Analysis comparing baseline and post-tremelimumab PBMC samples. The values were normalized to 1, to show increase and decrease after treatment in a comparable manner.
Figure 2
Figure 2. Rank-rank scatter plot analysis of all the TCR V-beta CDR3 sequences
Rank-rank scatter plot matching up baseline and post-tremelimumab samples from three representative patients. Each sequence was ranked according to clone abundance from highest frequency (rank 1 = 0) to lowest frequency. This provides a visual representation of the changes between baseline (x axis) and post-treatment (y axis) distributions. Example of A) an increase (GA5), B) a decrease (GA23), and C) of minimal change (GA33) in the TCR V-beta CDR3 repertoire. Scatter plots for all patients are shown in Supplemental Figure 1.
Figure 3
Figure 3. Richness and Shannon index for diversity
Differences in richness for total number of unique productive sequences (p=0.001) (A), and Shannon index for diversity of the repertoire (p=0.04) (B).
Figure 4
Figure 4
Correlation between fold-changes in top 25% abundant clones (x axis) vs fold-changes in CD4/CD8 density (y axis) at baseline and day 30–60, for CD4 intratumoral infiltration (ITI, A), CD4 peritumoral infiltration (PTI, B), CD8 ITI (C) and CD8 PTI (D).
Figure 5
Figure 5
Changes in number of unique TCR V-beta CDR3 sequences related to toxicity during the first 3 months of therapy with tremelimumab.
See this image and copyright information in PMC

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