Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade

Abstract

Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.

Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples

“…In melanoma patients, the peripheral TCR repertoire correlated with responses to checkpoint inhibitors [42][43][44], and similar results were reported for pancreatic ductal adenocarcinoma and other solid tumors [41]. Similarly, the evaluation of peripheral TCR repertoire of PD-1 + CD8+ lymphocytes also showed promising results as a non-invasive approach for selecting metastatic Melanoma TCR repertoire profiling is associated with immunotherapy response [42][43][44] Baseline frequency of CD14 + CD16-HLA-DRhi monocytes, CD69 + MIP-1β + NK cells, and PD-1 + CD56+ T cells are potential predictors of clinical response in patients treated with immunotherapy [45][46][47] The increase of central memory CD4+ T cells and the decrease of dysfunctional PD-1 + CD38hi CD8+ cells during immunotherapy are correlated with response. [48,49] Levels of circulating CD33 + CD11b + HLA-DR-myeloid derived suppressor and distinct CD4+ and CD8+ memory T cell subsets are correlated with survival of immunotherapy treated patients.…”

“…The predictive role of specific leukocyte subsets in patients undergoing anti-PD-1 and anti-CTLA4 immunotherapy has been investigated mostly in metastatic melanoma and lung cancer patients. The baseline frequency of CD14 + CD16-HLA-DRhi monocytes [45], CD69 + MIP-1β + NK cells [46], and PD-1 + CD56+ T cells [47] were reported to be predictors of clinical response in metastatic melanoma patients treated with anti-PD-1 immunotherapy. In the same setting, the post-treatment increase of the specific subset of central memory CD4+ T cells, harboring the CD27 + FAS-CD45RA-CCR7+ phenotype, was associated to prolonged clinical responses [48].…”

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

“… 32 Tumor immunogenicity scores are under evaluation as predictors for responses to ICI. 33 Previous studies already indicated peripheral blood immune cell subsets like PD-1 + CD56 + T cells 34 or CD4+ and CD8+ cells 35 to be associated with favorable outcome for advanced melanoma patients treated with ipilimumab directed against cytotoxic T lymphocyte antigen-4 (CTLA-4). Now we identified a liquid immune profile-based signature to predict response of patients with metastatic cancer to anti-PD-1/PD-L1 treatment at an early time point.…”

Development of a Flow Cytometry-Based Whole-Blood Prognostic Immune Signature in Metastatic Cancer Patients treated with immune checkpoint inhibitors

“…32 Tumor immunogenicity scores are under evaluation as predictors for responses to ICI. 33 Previous studies already indicated peripheral blood immune cell subsets like PD-1 + CD56 + T cells 34 or CD4+ and CD8+ cells 35 to be associated with favourable outcome for advanced melanoma patients treated with ipilimumab directed against cytotoxic T lymphocyte antigen-4 (CTLA-4). Now we identified a liquid immune profile-based signature to early predict response of metastatic cancer patients to anti-PD-1/PD-L1 treatment.…”