Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients

Abstract

The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analyzed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late stage melanoma patients. The proportions of baseline naïve and memory T cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p=0.029) and higher clinical response rates (p=0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio [HR]=1.5, p=0.033; and HR=1.9, p=0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p=0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 PD1+EM1 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 PD1+EM1 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.

Multicentre Harmonisation of a Six-Colour Flow Cytometry Panel for Naïve/Memory T Cell Immunomonitoring

“…In clinical cancer studies, due to the feasibility and reproducibility of blood compared to tumour tissue sampling, immune phenotyping of peripheral blood leukocyte subpopulations is considered as a valuable approach to explore systemic immunological markers that can facilitate patient selection and treatment decisions [14]. In particular, several papers reported clinical significance of naïve/memory T cell subsets as potential biomarkers with a prognostic and/or predictive of response to immunotherapy potential, in different cancer types, such as non-small cell lung cancer (NSCLC) [15] and melanoma [16,17]. Four functional T cell compartments can be defined in humans by the expression of CC-chemokine receptor 7 (CCR7) and CD45RA: naïve (N, CCR7+CD45RA+); central memory (CM, CCR7 +CD45RA−); effector memory (EM, CCR7−CD45RA−), and terminally differentiated effector (TD, CCR7−CD45RA+) T cells [18,19].…”

Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies

“…In particular, the predictive value of PD-L1 on tumour cells seems to be more robust with the anti-PD-1 antibody (nivolumab and pembrolizumab), and with regards to the advanced melanoma and NSCLC [35]. Other surrogate end-points have been investigated such as baseline neutrophil-tolymphocyte ratio or peripheral CD8 effector-memory type 1 T-cells [36,37] with an uncertainty on their use as surrogate markers for OS and prospective validations of these potential surrogates are required. Considering all these data together, the 50% rate of prediction on survival detected by our analysis seems to be relevant to define future studies on immune checkpoint inhibitors.…”

Informatics for Cancer Immunotherapy

“…Beyond immune checkpoint receptor or ligand expression, commonly proposed biomarkers for response to checkpoint blockade include mutation burden [354][355][356] , mismatch-repair status [357] , and loss of the interferon response pathway [358][359][360][361] . The composition of the gut microbiome [362,363] and overall immune system state (as inferred from peripheral blood samples) [364][365][366] have also been implicated.…”