Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma

doi:10.4251/wjgo.v16.i7.3256

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World Journal of Gastrointestinal Oncology

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World J Gastrointest Oncol. Jul 15, 2024; 16(7): 3256-3269
Published online Jul 15, 2024. doi: 10.4251/wjgo.v16.i7.3256

Table 1 Baseline patient data

Variables	T + A (n = 58)	T + L (n = 42)	T + S (n = 64)	T + D (n = 49)	P value
Age (≥ 55/< 55)	33/25	33/9	36/28	30/19	0.092
Sex (female/male)	10/48	6/36	7/57	8/41	0.768
Etiology					0.075
Hepatitis B virus	54	40	60	47
Hepatitis C virus	0	0	0	0
Others	4	2	4	2
AFP level (ng/mL)					0.084
≤ 400	26	14	18	24
> 400	32	28	46	25
ALT (U/L)					0.483
≤ 40	12	8	19	14
> 40	46	34	45	35
AST (U/L)					0.087
≤ 40	5	2	12	9
> 40	53	40	52	40
VEGF (pg/mL), mean (SD)	456.06 (216.38)	412.81 (163.02)	403.03 (168.45)	417.99 (170.99)	0.419
Cirrhosis
No	0	0	0	0
Yes	58	42	64	49
Child-Pugh class					0.102
A	41	24	49	29
B	17	18	15	20
Tumor size (cm)					0.103
≤ 5	34	18	41	23
> 5	24	24	23	26
Tumor number					0.338
Single	21	12	15	11
Multiple	37	30	49	38
Metastasis					0.091
Yes	18	20	16	19
No	40	22	48	30
BCLC stage					0.471
B	38	22	35	26
C	20	20	29	23

AFP: Alpha fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; T + A: Transcatheter arterial chemoembolization combined with apatinib group; T + L: Transcatheter arterial chemoembolization combined with lenvatinib group; T + S: Transcatheter arterial chemoembolization combined with sorafenib group; T + D: Transcatheter arterial chemoembolization combined with donafenib group; VEGF: Vascular endothelial growth factor; BCLC: Barcelona Clinic Liver Cancer.

Table 2 Peripheral blood lymphocyte profiles before and after treatment in different combination groups

Type	T + A			T + L			T + S			T + D
Type	Before treatment	After treatment	P value	Before treatment	After treatment	P value	Before treatment	After treatment	P value	Before treatment	After treatment	P value
Total T lymphocytes (%)	78.79 (9.22)	76.50 (10.59)	0.260	70.71 (10.78)	71.55 (9.20)	0.755	73.84 (11.88)	74.44 (9.47)	0.869	72.75 (13.79)	71.26 (14.45)	0.606
Suppressor/cytotoxic cells (%)	32.20 (13.03)	31.82 (14.55)	0.907	28.05 (12.29)	25.73 (7.82)	0.490	26.74 (12.65)	26.06 (8.73)	0.756	28.59 (14.91)	27.07 (13.53)	0.478
Helper/inducible cells (%)	39.04 (8.31)	37.98 (7.35)	0.608	40.89 (9.73)	32.54 (9.74)	0.003^a	42.05 (8.64)	44.06 (7.17)	0.434	34.70 (7.35)	35.93 (5.64)	0.446
Natural killer cell (%)	12.68 (8.13)	11.56 (8.28)	0.505	17.13 (8.63)	16.86 (8.16)	0.922	18.81 (11.28)	17.56 (9.27)	0.715	16.31 (11.20)	18.61 (12.75)	0.261
B lymphocytes (%)	7.20 (4.71)	9.43 (6.42)	0.093	10.68 (8.34)	10.82 (5.38)	0.952	5.58 (3.38)	5.96 (3.23)	0.707	10.30 (6.15)	10.40 (4.44)	0.933
Helper T cells/suppressor T cells	1.58 (1.20)	1.67 (1.27)	0.659	1.79 (1.25)	1.64 (0.93)	0.674	1.98 (0.99)	1.86 (0.63)	0.585	1.46 (0.54)	1.59 (0.61)	0.198
Regulatory cells (%)	11.65 (3.90)	11.60 (3.63)	0.918	10.47 (2.60)	11.79 (2.88)	0.110	10.04 (2.93)	10.31 (3.11)	0.789	12.23 (4.35)	10.78 (3.27)	0.013^a
Proportion of PD-1+ in mononuclei (%)	2.05 (4.13)	1.21 (2.89)	0.045^a	4.45 (6.24)	2.37 (6.43)	0.136	5.11 (8.10)	2.66 (6.40)	0.132	1.36 (4.86)	2.15 (6.24)	0.533
Proportion of PD-1+ in CD3+ cells (%)	2.43 (5.68)	1.85 (5.18)	0.563	6.93 (9.04)	3.79 (8.64)	0.205	6.91 (10.95)	3.48 (8.89)	0.071	1.69 (6.48)	2.79 (8.01)	0.330
Proportion of PD-1+ in CD4+ cells (%)	1.69 (4.39)	1.72 (5.14)	0.974	6.11 (8.56)	3.16 (7.42)	0.144	8.06 (12.81)	3.91 (10.43)	0.146	2.00 (8.42)	2.62 (7.94)	0.660
Proportion of PD-1+ in CD8+ cells (%)	3.32 (8.42)	1.86 (5.36)	0.262	7.92 (11.64)	4.60 (10.61)	0.262	3.36 (6.86)	1.98 (7.22)	0.375	1.13 (4.02)	2.12 (6.05)	0.292
Absolute count of total lymphocytes (/uL)	1537.33 (650.17)	1349.96 (534.78)	0.154	1248.86 (442.71)	1624.48 (602.20)	0.032^a	1555.82 (503.27)	1319.00 (374.04)	0.148	1891.05 (784.70)	1721.86 (466.61)	0.378
Absolute T lymphocyte count (/uL)	1194.63 (461.58)	1058.63 (467.70)	0.223	898.57 (347.46)	1143.43 (436.88)	0.058	1137.41 (484.47)	976.18 (230.22)	0.266	1251.73 (531.50)	1270.27 (452.22)	0.860
CD4+T lymphocyte absolute count (/uL)	625.46 (346.62)	488.96 (184.78)	0.027^a	421.43 (38.52)	603.24 (62.16)	0.009^a	628.12 (184.95)	579.65 (173.29)	0.425	627.45 (198.58)	590.09 (464.05)	0.700
CD8+T lymphocyte absolute count (/uL)	492.25 (266.83)	457.58 (368.59)	0.652	379.71 (130.84)	502.71 (267.30)	0.023^a	425.24 (327.35)	340.24 (125.24)	0.294	390.64 (183.19)	530.18 (169.23)	0.001^a
Absolute NK cell count (/uL)	214.25 (217.71)	156.75 (143.46)	0.112	299.10 (233.67)	201.76 (113.38)	0.114	333.12 (238.31)	258.47 (191.34)	0.323	288.41 (223.55)	384.86 (229.53)	0.039^a
Absolute B cell count (/uL)	109.21 (95.35)	127.29 (89.20)	0.333	178.76 (153.83)	134.33 (77.23)	0.285	80.18 (46.41)	74.82 (46.18)	0.720	179.60 (108.93)	164.73 (93.09)	0.650

^aP < 0.05.

T + A: Transcatheter arterial chemoembolization combined with apatinib group; T + L: Transcatheter arterial chemoembolization combined with lenvatinib group; T + S: Transcatheter arterial chemoembolization combined with sorafenib group; T + D: Transcatheter arterial chemoembolization combined with donafenib group; PD-1: Programmed cell death protein 1; NK: Natural killer cell.

Table 3 Univariate and multivariate Cox regression analyses for progression-free survival

Variables	Univariate analysis		Multivariate analysis
Variables	HR (95%CI)	P value	HR (95%CI)	P value
Age	0.989 (0.968-1.010)	0.302
Sex	0.964 (0.538-1.725)	0.901
Etiology	1.242 (0.537-2.873)	0.612
AFP	1.318 (0.845-2.057)	0.224
ALT	1.002 (0.999-1.005)	0.309
AST	1.001 (0.999-1.003)	0.518
VEGF	1.000 (0.999-1.001)	0.798
Child-Pugh class	1.135 (0.721-1.788)	0.585
ECOG score
0	0.925 (0.338-2.534)	0.880
1	0.980 (0.562-1.708)	0.943
Tumor size	1.011 (1.004-1.019)	0.002^a	1.009 (1.001-1.017)	0.023^a
Tumor number	0.974 (0.860-1.103)	0.677
Metastasis	0.947 (0.578-1.554)	0.831
BCLC stage	1.436 (0.914-2.254)	0.116
Treatment methods
T + A	0.722 (0.396-1.317)	0.288
T + L	0.608 (0.321-1.152)	0.608
T + S	0.586 (0.300-1.145)	0.118
Total T lymphocytes	0.986 (0.966-1.008)	0.211
Suppressor/cytotoxic cells	0.998 (0.981-1.016)	0.859
Helper/inducible cells	0.976 (0.954-0.998)	0.033^a	0.982 (0.959-1.006)	0.133
Natural killer cell	1.016 (0.991-1.043)	0.210
B lymphocytes	1.024 (0.984-1.065)	0.252
Helper T cells/suppressor T cells	1.017 (0.823-1.257)	0.873
Regulatory cells	1.100 (1.033-1.172)	0.003^a	1.063 (0.989-1.144)	0.098
Proportion of PD-1+ in peripheral blood mononuclei	1.014 (0.975-1.054)	0.498
Proportion of PD-1+ in CD3+ cells	1.011 (0.984-1.039)	0.410
Proportion of PD-1+ in CD4+ cells	1.010 (0.985-1.037)	0.435
Proportion of PD-1+ in CD8+ cells	0.975 (0.946-0.999)	0.040^a	0.966 (0.938-0.995)	0.022^a
Absolute count of total lymphocytes	1.000 (1.000-1.000)	0.782
Absolute T lymphocyte count	1.000 (0.999-1.000)	0.451
Absolute count of CD3+CD4+ lymphocytes	1.000 (0.999-1.001)	0.477
Absolute count of CD3+CD8+ lymphocytes	0.998 (0.997-0.999)	0.002^a	0.998 (0.997-0.999)	0.001^a
CD4/CD8 ratio	0.934 (0.741-1.177)	0.564
Absolute NK cell count	1.001 (1.000-1.002)	0.168
Absolute B cell count	1.002 (1.000-1.004)	0.085

^aP < 0.05.

T + A: Transcatheter arterial chemoembolization combined with apatinib group; T + L: Transcatheter arterial chemoembolization combined with lenvatinib group; T + S: Transcatheter arterial chemoembolization combined with sorafenib group; AFP: Alpha fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; ECOG: Eastern Cooperative Oncology Group; VEGF: Vascular endothelial growth factor; PD-1: Programmed cell death protein 1; NK: Natural killer cell; HR: Hazard ratio; CI: Confidence interval.

Table 4 Univariate and multivariate Cox regression analyses for overall survival

Variables	Univariate analysis		Multivariate analysis
Variables	HR (95%CI)	P value	HR (95%CI)	P value
Age	0.994 (0.972-1.015)	0.554
Sex	1.273 (0.710-2.282)	0.418
Etiology	1.444 (0.619-3.368)	0.396
AFP	1.215 (0.769-1.919)	0.405
ALT	1.062 (0.617-1.827)	0.828
AST	1.002 (1.000-1.004)	0.064
VEGF	1.000 (0.999-1.001)	0.780
Child-Pugh class	0.947 (0.594-1.512)	0.821
ECOG score
0	1.029 (0.393-2.690)	0.954
1	0.884 (0.490-1.595)	0.683
Tumor size	1.011 (1.003-1.020)	0.005^a	1.010 (1.001-1.016)	0.032^a
Tumor number	0.954 (0.842-1.081)	0.461
Metastasis	0.928 (0.556-1.548)	0.774
BCLC stage	1.209 (0.760-1.924)	0.423
Treatment methods
T + A	0.926 (0.499-1.720)	0.809
T + L	0.781 (0.408-1.492)	0.453
T + S	0.698 (0.358-1.360)	0.291
Total T lymphocytes	0.990 (0.968-1.012)	0.379
Suppressor/cytotoxic cells	0.992 (0.974-1.011)	0.421
Helper/inducible cells	0.999 (0.976-1.021)	0.903
Natural killer cell	1.007 (0.982-1.032)	0.590
B lymphocytes	1.031 (0.988-1.076)	0.164
Helper T cells/suppressor T cells	1.088 (0.885-1.337)	0.426
Regulatory cells	1.082 (1.008-1.161)	0.029^a	1.074 (1.001-1.152)	0.046^a
Proportion of PD-1+ in peripheral blood mononuclei	1.012 (0.972-1.054)	0.561
Proportion of PD-1+ in CD3+ cells	1.011 (0.983-1.041)	0.432
Proportion of PD-1+ in CD4+ cells	1.007 (0.981-1.034)	0.618
Proportion of PD-1+ in CD8+ cells	0.989 (0.963-1.015)	0.402
Absolute count of total lymphocytes	1.000 (1.000-1.000)	0.612
Absolute T lymphocyte count	1.000 (0.999-1.000)	0.784
Absolute count of CD3+CD4+ lymphocytes	1.000 (0.999-1.001)	0.926
Absolute count of CD3+CD8+ lymphocytes	0.999 (0.998-1.000)	0.096
CD4/CD8 ratio	0.992 (0.795-1.239)	0.945
Absolute NK cell count	1.000 (0.999-1.001)	0.527
Absolute B cell count	1.003 (1.001-1.005)	0.017^a	1.002 (1.000-1.004)	0.108

^aP < 0.05.

AFP: Alpha fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; ECOG: Eastern Cooperative Oncology Group; OS: Overall survival; T + A: Transcatheter arterial chemoembolization combined with apatinib group; T + L: Transcatheter arterial chemoembolization combined with lenvatinib group; T + S: Transcatheter arterial chemoembolization combined with sorafenib group; VEGF: Vascular endothelial growth factor; PD-1: Programmed cell death protein 1; NK: Natural killer cell; HR: Hazard ratio; CI: Confidence interval.

Citation: Guo Y, Li RC, Xia WL, Yang X, Zhu WB, Li FT, Hu HT, Li HL. Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16(7): 3256-3269
URL: https://www.wjgnet.com/1948-5204/full/v16/i7/3256.htm
DOI: https://dx.doi.org/10.4251/wjgo.v16.i7.3256