Tumor-associated Macrophages and Macrophage-Related Immune Checkpoint Expression in Sarcomas

Early trials for immune checkpoint inhibitors in sarcomas have delivered mixed results, and efforts to improve outcomes now look to combinatorial strategies with novel immunotherapeutics, including some that target macrophages. To enhance our understanding of the sarcoma immune landscape, we quantified and characterized tumor-associated macrophage infiltration and expression of the targetable macrophage-related immune checkpoint CD47/SIRPα across sarcoma types. We surveyed immunohistochemical expression of CD68, CD163, CD47, and SIRPα in tissue microarrays of 1242 sarcoma specimens (spanning 24 types). Non-translocation sarcomas, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had significantly higher counts of both CD68+ and CD163+ macrophages than translocation-associated sarcomas. Across nearly all sarcoma types, macrophages outnumbered tumor-infiltrating lymphocytes and CD163+ (M2-like) macrophages outnumbered CD68+ (M1-like) macrophages. These findings were supported by data from The Cancer Genome Atlas, which showed a correlation between increasing macrophage contributions to immune infiltration and several measures of DNA damage. CD47 expression was bimodal, with most cases showing either 0% or >90% tumor cell staining, and the highest CD47 scores were observed in chordoma, angiosarcoma, and pleomorphic liposarcoma. SIRPα scores correlated well with CD47 expression. Given the predominance of macrophage infiltrates over tumor-infiltrating lymphocytes, the bias toward M2-like (immunosuppressive) macrophage polarization, and the generally high scores for CD47 and SIRPα, macrophage-focused immunomodulatory agents, such as CD47 or IDO-1 inhibitors, may be particularly worthwhile to pursue in sarcoma patients, alone or in combination with lymphocyte-focused agents

[OP.7D.07] INFLUENCE OF RENAL SYMPATHETIC DENERVATION ON BLOOD PRESSURE VARIABILITY: EXPERIENCE AT 11 EUROPEAN EXPERT CENTERS.

OBJECTIVE: Sympathetic tone is one of the main determinants of blood pressure (BP) variability. The aim of our study was to assess the changes in BP variability after renal sympathetic denervation (RDN) in resistant hypertensive patients, and, conversely, to look for the predictive value of baseline BP variability on mean BP changes after RDN. DESIGN AND METHOD: Twenty-four hour BP measurements were analyzed in 167 resistant hypertensive patients recruited at 11 expert centers within the European Network Coordinating research on Renal Denervation (ENCOReD) (mean age 56.7 years; 40 % women; mean baseline office BP: 172/98 mmHg; 24-h ambulatory BP: 152/90 mmHg), both at baseline and after RDN. Blood pressure variability was assessed by the weighted standard deviation (SDw), average real variability (ARV), coefficient of variation (CV) and variability independent of the mean (VIM) of 24-h ambulatory BP. RESULTS: After an average follow up of 6.7 months, mean office and 24-h ambulatory BP fell by 15.4/6.6 mmHg and 5.5/3.7 mmHg respectively (P < 0.0001 for both). Whereas no significant changes in ARV or CV were observed, SDw and VIM for 24-h systolic BP decreased by -1.29 mmHg (95%CI: -2.17 to -0.42; P < 0.01) and -1.11 mmHg (95%CI: -1.92 to -0.30; P < 0.01), respectively. Decrease in these systolic BP variability estimates remained significant in multivariable-adjusted analyses and was paralleled by similar changes for 24-h diastolic BP. Finally, baseline SDw (P = 0.0006), ARV (P = 0.012) and VIM (P = 0.04) were significantly correlated with mean changes in diastolic - but not systolic - BP after RDN. CONCLUSIONS: Renal denervation was associated with a significant decrease in BP variability independent of the mean, which in the long term may decrease cardiovascular risk. Furthermore, baseline BP variability was predictive of diastolic BP changes after RDN. These results are consistent with the known influence of sympathetic nervous system on BP variability and peripheral vascular resistances. Our findings need confirmation in randomized controlled studies testing second-generation RDN catheters, preferably including younger patients with higher sympathetic tone and less advanced vascular damage

Blood pressure response to renal denervation is correlated with baseline blood pressure variability: a patient-level meta-analysis.

Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN. We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatment-resistant hypertension patients (40% women; age, 56.7 years; mean 24-h BP, 152/90 mmHg) recruited at 11 expert centers. BP variability was assessed by weighted SD [SD over time weighted for the time interval between consecutive readings (SDiw)], average real variability (ARV), coefficient of variation, and variability independent of the mean (VIM). Mean office and 24-h BP fell by 15.4/6.6 and 5.5/3.7 mmHg, respectively (P < 0.001). In multivariable-adjusted analyses, systolic/diastolic SDiw and VIM for 24-h SBP/DBP decreased by 1.18/0.63 mmHg (P ≤ 0.01) and 0.86/0.42 mmHg (P ≤ 0.05), respectively, whereas no significant changes in ARV or coefficient of variation occurred. Furthermore, baseline SDiw (P = 0.0006), ARV (P = 0.01), and VIM (P = 0.04) predicted the decrease in 24-h DBP but not 24-h SBP after RDN. RDN was associated with a decrease in BP variability independent of the BP level, suggesting that responders may derive benefits from the reduction in BP variability as well. Furthermore, baseline DBP variability estimates significantly correlated with mean DBP decrease after RDN. If confirmed in younger patients with less arterial damage, in the absence of the confounding effect of drugs and drug adherence, baseline BP variability may prove a good predictor of BP response to RDN