Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice

Figures & data

Table 1. Characteristics of metastatic melanoma patients.

	All Patients	No β-blocker	β1-blocker	Pan β-blocker	p value
	N = 195	N = 133	N = 45	N = 17
Age at start of immunotherapy treatment
Mean	60.7	60.1	62.3	61.5
(SD)	(14.7)	(14.7)	(14.4)	(16.3)	0.6294
Median	61.8	61.4	63.1	69.6
(Range)	(22–92)	(22–92)	(30–89)	(23–80)
Sex
Male	124 (63.6%)	83 (62.4%)	31 (68.9%)	10 (58.8%)	0.6726
Female	71 (36.4%)	50 (37.6%)	14 (31.1%)	7 (41.2%)
Stage at Initial Diagnosis^*
0	2 (1.2%)	2 (1.2%)	0 (0%)	0 (0%)
I	31 (19.1%)	22 (20.2%)	7 (17.9%)	2 (14.3%)
II	40 (24.7%)	27 (24.8%)	10 (25.6%)	3 (21.4%)
III	57 (35.2%)	38 (34.9%)	13 (33.3%)	6 (42.9%)
IV	32 (19.8%)	20 (18.3%)	9 (23.1%)	3 (21.4%)	0.9830

Descriptive characteristics of the patients in this study are summarized overall and by β-blocker usage. Where not indicated as SD or range, values represent the number of patients followed by the percentage of that column in parenthesis. The p-values were obtained using nonparametric Kruskal-Wallis tests or Fisher's exact tests with p<0.05 considered significant.

* Note that all patients had metastatic disease at the time of immunotherapy regardless of staging at diagnosis.

Figure 1. Malignant melanoma patients receiving pan β-blockers have prolonged survival following immunotherapy. Overall survival following the initiation of immunotherapy treatment was determined for melanoma patients treated with at least one immunotherapy (IL-2, αCTLA-4, αPD-1). Patients were stratified based on specific β₁AR antagonist use, non-specific pan βAR antagonist use or no β-blocker use. N = 195; * = p <0.05 determined by log rank test; NS = not significant.

Figure 2. Propranolol improves tumor control in mice treated with immunotherapy. (A) Experimental schema. When applicable, tumor-bearing mice received 10mg/kg propranolol (pan β-blocker) daily for three weeks, 200μg αPD-1 twice a week for three weeks and/or 120,000 IU IL-2 twice a day for two cycles of five days on, two days off. An equivalent volume of PBS was given daily to control mice. Mice were treated with (B) PBS control, (C) αPD-1, (D) IL-2, (E) αPD-1/IL-2, (F) Propranolol, (G) Propranolol + αPD-1, (H) Propranolol + IL-2, (I) Propranolol + αPD-1/IL-2. Days 15 and 30 are indicated with long- and short-dashed lines. N = 7–8/group; p values determined by mixed linear models; pairwise comparison to untreated: ** p < 0.01, **** p < 0.0001; pairwise comparison to propranolol: ˆˆ p < 0.01, ˆˆˆ p <0.001; pairwise comparison between immunotherapy and propranolol + immunotherapy: @ p < 0.05, @@ p < 0.01. (J) Survival analysis. N = 7/group; p values determined by log rank test. Data are representative of two experiments. MS = median survival.

Figure 3. β₂AR-selective blockade improves immunotherapy against melanoma. Mice were treated as indicated in Figure 2 with (A) PBS control, (B) Metoprolol (β₁AR selective antagonist), (C) ICI 118, 551 (β₂AR selective antagonist), (D) αPD-1/IL-2, (E) Metoprolol + αPD-1/IL-2, (F) ICI 118, 551 + αPD-1/IL-2. Days 15 and 30 are indicated with long- and short-dashed lines, respectively. N = 5–8/group; p values determined by mixed linear models; pairwise comparison to untreated: *** p < 0.001; pairwise comparison to same β-blocker: ˆ p < 0.05, ˆˆˆˆ p < 0.0001; pairwise comparison between immunotherapy alone and β-blocker + immunotherapy: @ p < 0.05. (G) Survival analysis. The median survival (days) is listed in parenthesis for each group. N = 5–7/group; p values determined by log rank test; NS = not significant; MS = median survival.