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Figure S4 from Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma

figure

posted on 2023-04-03, 22:41 authored by Sabrina A. Hogan, Anaïs Courtier, Phil F. Cheng, Nicoletta F. Jaberg-Bentele, Simone M. Goldinger, Manuarii Manuel, Solène Perez, Nadia Plantier, Jean-François Mouret, Thi Dan Linh Nguyen-Kim, Marieke I.G. Raaijmakers, Pia Kvistborg, Nicolas Pasqual, John B.A.G. Haanen, Reinhard Dummer, Mitchell P. Levesque

3D representation of the TCR diversity. Each peak represents a rearrangement between a given V gene family and a J segment. X axis: TRBV, y axis: TRBJ, z axis relative intensity. The table shows the top 10 rearrangements, listed in decreasing order of contribution to the global repertoire. Contribution is calculated based on the ratio between individual rearrangement intensity and the sum of all rearrangements intensities. A) Immune maps of the patients eventually responding to anti-PD1 therapy (PD and CR). B) Immune maps of the patients who eventually did not respond to anti-PD1 therapy (PD).

Funding

European Training Network MELGEN

History

ARTICLE ABSTRACT

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A receiver operating characteristic curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but, on the other hand, predicted a poor response to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.