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

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 DE 50 , 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 ¼ 42) or anti-PD1 (n ¼ 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 DE 50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE 50 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 DE 50 as the only independent predictive factor for response to anti-CTLA4 therapy (P ¼ 0.03) and anti-PD1 therapy (P ¼ 0.001). Fisher exact tests confirmed the association of low DE 50 with response in the anti-CTLA4 (P ¼ 0.041) and the anti-PD1 cohort (P ¼ 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCRbased method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

“…Previous studies have shown TCR repertoire diversity in the peripheral blood to be an indicator of prognosis, and high TCR repertoire diversity might indicate favorable outcomes [23,27,28]. Our study supplemented the prognostic value of TCR repertoire diversity in RETdriven lung cancers but disagree with the latter notion.…”

“…The T cell receptor (TCR) repertoire has recently emerged as a novel biomarker [23,24]. Previous pilot studies showed that tumor-infiltrated TCR clonality [25] and peripheral blood T cell receptor repertoire diversity [26][27][28] could have a potential role as predictors of the response to ICI therapy. We conducted multiplex PCR amplification on complementarity-determining region 3 (CDR3), a hypervariable region of the TCR β chain that is unique to each TC R [29] as previously described [27].…”

CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer

“…The diversity of the TCR repertoire, which reflects the clonal composition of T cells may be a predictive marker of response to cancer immunotherapy 44,45 . Previous reports have shown that anti-CTLA-4 treatment leads to a significant broadening of CD8 + T-cell responses specific for melanoma and an increased diversity of T cells in blood after CTLA-4 blockade 46,47 .…”

Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

“…The TCR clonality of both CD4 + and CD8 + T cells is more restricted than in healthy people, and broader T cell responses with greater diversity of CD4 + blood T cell clones may predict the longer survival of patients with melanoma treated with anti‐CTLA4 or PD‐1 antibodies . Many studies have shown that peripheral blood TCR diversity can be used to predict the efficacy of immunotherapy . Therefore, PEG‐rhG‐CSF may improve the efficacy of immunotherapy by increasing peripheral blood TCR diversity; however, further clinical studies are needed to confirm this.…”

“…19 Many studies have shown that peripheral blood TCR diversity can be used to predict the efficacy of immunotherapy. 17,21,33,34 Therefore, PEG-rhG-CSF may improve the efficacy of immunotherapy by increasing peripheral blood TCR diversity; however, further clinical studies are needed to confirm this. We found no MH overlap on day 3, and day 8-10 showed a significant difference between groups.…”