Impact of endogenous glucocorticoid on response to immune checkpoint blockade in patients with advanced cancer

Abstract

BackgroundPrevious studies indicate that exogenous use of glucocorticoid (GC) affects immune checkpoint inhibitor (ICI) efficacy. However, there is a paucity of clinical data evaluating the direct impact of endogenous GC on the efficacy for cancer patients with immune checkpoint blockade.MethodsWe first compared the endogenous circulating GC levels in healthy individuals and patients with cancer. We next retrospectively reviewed patients with advanced cancer with PD-1/PD-L1 inhibitor alone or combination therapy in a single center. The effects of baseline circulating GC levels on objective response rate (ORR), durable clinical benefit (DCB), progression‐free survival (PFS), and overall survival (OS) were analyzed. The association of the endogenous GC levels with circulating lymphocytes, cytokines levels, and neutrophil to lymphocyte ratio, and tumor infiltrating immune cells, were systematically analyzed.ResultsThe endogenous GC levels in advanced cancer patients were higher than those in early-stage cancer patients as well as healthy people. In the advanced cancer cohort with immune checkpoint blockade (n=130), patients with high baseline endogenous GC levels (n=80) had a significantly reduced ORR (10.0% vs 40.0%; p<0.0001) and DCB (35.0% vs 73.5%, p=0.001) compared to those with low endogenous GC levels (n=50). The increased GC levels was significantly associated with reduced PFS (HR 2.023; p=0.0008) and OS (HR 2.809; p=0.0005). Moreover, statistically significant differences regarding PFS, and OS were also detected after propensity score matching. In a multivariable model, the endogenous GC was identified as an independent indicator for predicting PFS (HR 1.779; p=0.012) and OS (HR 2.468; p=0.013). High endogenous GC levels were significantly associated with reduced lymphocytes (p=0.019), increased neutrophil to lymphocyte ratio (p=0.0009), and increased interleukin-6 levels (p=0.025). Patients with high levels of endogenous GC had low numbers of tumor infiltrating CD3+ (p=0.001), CD8+ T (p=0.059), and CD4+ T (p=0.002) cells, and the numbers of circulating PD-1+ NK cells (p=0.012), and the ratio of CD8+PD-1+ to CD4+PD-1+ (p=0.031) were higher in patients with high levels of endogenous GC compared to low levels of endogenous GC.ConclusionBaseline endogenous GC increase executes a comprehensive negative effect on immunosurveillance and response to immunotherapy in real-world cancer patients accompanied with cancer progression.

Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis

“…Moreover, endogenous glucocorticoids (GCs) were reported to be indispensable for PD-1 induction on NK cells ( 58 ). To our knowledge, our study is the first reporting increased PD-1 expression on lymphocytes in mucosal tissue following glucocorticoid treatment, which opens new questions especially with increasing rates of oral glucocorticoid prescriptions associated with immune check point inhibitor use in a clinical setting ( 59 , 60 ), where higher endogenous glucocorticoid levels are associated with worse response rates to immune check point blockade ( 61 ). Our findings may be of importance considering that a single trial found that almost 40% of patients under immune check point inhibitor treatment for melanoma receive GCs at least for a short term ( 60 ).…”

Subclone from CT26 resistant to anti-PD-1 therapy associated with increased expression of genes related to glucocorticoids

“…GCs can potentiate the inhibitory effect of PD-1 by upregulating its expression on tumor-infiltrating T and NK cells. Cui et al [ 25 ] found in a study on gastric cancer that, compared with non-responsive gastric cancer patients, responsive gastric cancer patients still have lower endogenous GC levels. Nascentes et al [ 11 ] also found in a study on melanoma that the expression of genes involved in GC activation ( Hsd11b1 ) was significantly higher in ICI non-responders than in responders.…”

Histological sarcomatoid transformation in a lung adenocarcinoma patient following immune checkpoint blockade

“…IHC staining was performed according to our previously published procedures. 10 The tumor specimens were reacted overnight at 4°C with primary mouse anti-human monoclonal CD8 and CD4 antibodies (1:200 solution; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and with the PD-L1 antibody (22C3 pharmDx assay; Agilent, Carpinteria, CA, USA). After incubating with a biotin-conjugated secondary antibody for 30 min at room temperature, the sections were further treated with an avidin–biotin–peroxidase complex system (RTU VECTASTAIN Kit; Vector Laboratories, Burlingame, CA, USA).…”

“…For multiplex immunofluorescence staining, FFPE blocks were first heated at 65°C for 3 h according to the previous procedures. 10 The slides were then dewaxed, rehydrated, and fixed using a Leica BOND RX Auto Stainer (Leica Biosystems, YTAn00042, Buffalo Grove, IL) Subsequently, the slides were stained with six antibodies: anti-CD4 (ab133616; Abcam), anti-CD8 (MA1-80231; Thermo Fisher Scientific), anti-CD68 (MA5-12407; Thermo Fisher Scientific), anti-FoxP3 (ab215206; Abcam), anti-PD-L1 (13684S; Cell Signaling Technology), and anti-pan keratin (sc-81714; Santa Cruz Biotechnology), followed by incubation with horseradish peroxidase-conjugated secondary antibody and tyramide signal amplification. Finally, the slides were stained with 4′-6′-diamidino-2-phenylindole for 10 min at a 9:125 dilution.…”