Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients ...show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival.
Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n = 130; one prospectively collected multicentric validation cohort, n = 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay.
Melanoma patients showed higher serum concentrations of PD-1 (P = 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P = 0.014, P = 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P = 0.0081, P = 0.053) and overall survival (OS; P = 0.055, P = 0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of anti-PD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P = 0.037), PFS (P = 0.048), and OS (P = 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P = 0.019; PFS, P = 0.038; OS, P = 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P = 0.010) and OS (P = 0.003) in patients treated with PD-1 inhibitors.
Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.
•Melanoma patients show higher serum concentrations of PD-1 and PD-L1 than healthy controls.•High serum PD-1 and PD-L1 at baseline are associated with an impaired therapy response to anti-PD-1, but not to anti-BRAF.•Serum PD-1 and PD-L1 at baseline correlate with survival (PFS and OS) upon therapy with anti-PD-1, but not with anti-BRAF.•Multivariable analysis demonstrates serum PD-1/PD-L1 as an independent predictor of survival upon anti-PD-1 therapy.•Serum PD-1 and PD-L1 might be used to select melanoma patients for PD-1-based versus BRAF-based therapy.
Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic ...lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N=51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (P<0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA>990 pg/ml (P=0.014), sMICB>200 pg/ml (P=0.0001), and sULBP2>105 pg/ml (P<0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P=0.002), sULBP2 (P=0.002) and ZAP-70 (P=0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels>105 pg/ml were strongly associated (P=0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression.
The HLA‐G molecule belongs to the family of nonclassical human leukocyte antigen (HLA) class I. At variance to classical HLA class I, HLA‐G displays (i) a low number of nucleotide variations within ...the coding region, (ii) a high structural diversity, (iii) a restricted peptide repertoire, (iv) a limited tissue distribution and (v) strong immune‐suppressive properties. The physiological HLA‐G surface expression is restricted to the maternal–fetal interface and to immune‐privileged adult tissues. Soluble forms of HLA‐G (sHLA‐G) are detectable in various body fluids. Cellular activation and pathological processes are associated with an aberrant or a neo‐expression of HLA‐G/sHLA‐G. Functionally, HLA‐G and its secreted forms are considered to be key players in the induction of short‐ and long‐term tolerance. Thus, its unique expression profile and tolerance‐inducing functions render HLA‐G/sHLA‐G an attractive biomarker to monitor the systemic health/disease status and disease activity/progression for clinical approaches in disease management and treatments. Here, we place emphasis on (i) the current status of the tolerance‐inducing functions by HLA‐G/sHLA‐G, (ii) the current complexity to implement this molecule as a meaningful clinical biomarker regarding the three dimensions of structural diversity (monomers, dimers and HLA‐G‐expressing extracellular vesicles) with its functional implications, and (iii) novel and future approaches to detect and quantify sHLA‐G structures and functions.
BACKGROUND Soluble HLA-G (sHLA-G) has been suggested as a non-invasive marker for embryo selection to improve pregnancy rates after assisted reproduction technique (ART). Our study aimed at the ...identification of parameters influencing the detection of sHLA-G in embryo cultures (ECs) and at the prognostic relevance of sHLA-G in a multi-centre study. METHODS In total 4212 EC from 2364 cycles were randomly collected from 29 German ART centres and analysed for sHLA-G by Luminex®-based technology. RESULTS Among test and culture conditions, only the cleavage stage of the embryo was identified as an independent factor for sHLA-G detection (P < 0.001). Overall, sHLA-G was significantly associated with pregnancy after ART P < 0.001; odds ratio: 2.0 (95% CI: 1.7–2.4), suggesting that sHLA-G testing might improve the pregnancy rate from 30 to 40%. Importantly, the sHLA-G status of embryos could be associated with pregnancy after single embryo transfer P = 0.002; odds ratio: 3.3 (95% CI: 1.5–6.8) doubling the probability of pregnancy rate to 26% after sHLA-G testing. The patient's age, number of transferred embryos, morphological grading EXP(B): 4.3 (95% CI: 2.1–8.9) of embryos and sHLA-G status EXP(B): 2.3 (95% CI: 1.8–3.1) were independent predictors of pregnancy, with the latter two being most powerful. CONCLUSIONS This study provides significant evidence that the morphological scoring system is still the best strategy for the selection of embryos but that sHLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.
During pregnancy the fetus represents a semi-allograft. Both membrane-bound and soluble forms of the nonclassic human leukocyte antigen (HLA)-G protect the fetus from maternal immune attack. To ...assess the relevance of soluble HLA-G (sHLA-G) levels in the maternal circulation for the occurrence of characteristic pregnancy disorders, we analyzed sHLA-G plasma levels of women with normal and pathological pregnancies. Compared to normal pregnancy, significantly increased sHLA-G levels were detected in women delivered preterm because of intrauterine activation (uncontrollable labor, rupture of fetal membranes, cervical insufficiency) and women with Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome. Contrary to these disorders, the sHLA-G levels in women with placental abruption were more than three times lower than in normal pregnancy (p < .0001). Nonparametric discriminant analysis showed that women with sHLA-G levels below 9.95 ng/mL had a relative risk of 7.12 for the development of placental abruption during further course of pregnancy. These results suggest that the occurrence of pregnancy-associated diseases is strongly influenced by maternal sHLA-G plasma levels.
Our clinical studies revealed significantly increased soluble HLA-G (sHLA-G) plasma levels in patients suffering from malignant melanoma, glioma, breast and ovarian cancer. Specific ELISpot assays ...demonstrate that sHLA-G molecules expressing intron-4 sequences are preferentially secreted by peripheral blood monocytes. In vitro, the sHLA-G secretion of monocytes and tumor cells was strongly enhanced by TH1 cytokines like IFN-α, -β, -γ whereas TH2 cytokines (e.g. IL-4, -10) had minor effects. As sHLA-G can inhibit the functions of T and NK cells high concentration of these molecules should systemically or at the tumor side reduce the immune surveillance and thus favour the progression of cancer.
PDF
