Prognostic significance of PD-L1/PD-1 co-expression and CXCR3-driven inflammatory signatures in Egyptian patients with lymphoproliferative neoplasms

Table 1 Demographic characteristics of patients with lymphoproliferative neoplasms and healthy controls (n = 180), mean ± SD/n (%)

Variable	Patients (n = 90)	Controls (n = 90)
Age (years)	59.17 ± 7.72	58.19 ± 7.72
Sex
Male	34 (37.8)	42 (46.7)
Female	56 (62.2)	48 (53.3)

t-test for age, χ² test for sex. Patients and controls were matched for age and sex; therefore, no statistical comparisons were performed for these variables.

Table 2 Clinical characteristics of patients with lymphoproliferative neoplasms (n = 90), n (%)

Variable
Lymph node involvement	53 (58.9)
Bone marrow involvement	32 (35.6)
Hepatomegaly	12 (13.3)
Splenomegaly	7 (7.8)
Ann Arbor stage
Stage I	19 (21.1)
Stage II	26 (28.9)
Stage III	7 (7.8)
Stage IV	38 (42.2)

Table 3 Hematological, biochemical, and inflammatory parameters in patients and controls (n = 180), mean ± SD

Parameter	Patients (n = 90)	Controls (n = 90)	P value
Hematological parameters
Hemoglobin (g/dL)	8.31 ± 1.03	13.41 ± 0.77	< 0.001c
Platelet count (× 109/L)	95.4 ± 9.87	258.3 ± 60.98	< 0.001c
Total leukocyte count (× 109/L)	20.74 ± 21.78	7.43 ± 1.81	0.209
Neutrophil count (× 109/L)	3.1 ± 2.79	4.16 ± 1.05	0.005b
Lymphocyte count (× 109/L)	15.99 ± 17.73	2.36 ± 0.73	0.010a
Monocyte count (× 109/L)	0.591 ± 0.233	0.500 ± 0.150	0.774
Eosinophil count (× 109/L)	0.244 ± 0.259	0.268 ± 0.165	0.008b
Biochemical parameters
LDH (U/L)	615.9 ± 69.72	121.6 ± 18.05	< 0.001c
CRP (mg/L)	28.2 ± 12.22	3.43 ± 1.61	< 0.001c
Ferritin (ng/mL)	540 ± 84.64	82.2 ± 40.81	< 0.001c
Transferrin saturation (%)	36.87 ± 7.3	64.67 ± 16.13	< 0.001c
Beta-2 microglobulin (mg/L)	3.8 ± 1.2	1.8 ± 0.5	< 0.001c
Albumin (g/dL)	3.5 ± 0.6	4.3 ± 0.4	< 0.001c
ESR (mm/hour)	45.0 ± 15.0	12.0 ± 4.0	< 0.001c
Inflammatory indices
SII	30971.8 ± 14428.6	455.0 ± 211.9	< 0.001c
SIRI	250.7 ± 200.2	1.1 ± 0.5	< 0.001c
Platelet-to-lymphocyte ratio	29.6 ± 23.97	115.0 ± 38.33	< 0.001c
Neutrophil-to-lymphocyte ratio	0.32 ± 0.14	1.68 ± 0.58	< 0.001c
Ferritin-to-lymphocyte ratio	0.18 ± 0.17	0.04 ± 0.02	0.016a
White cell-to-lymphocyte ratio	1.44 ± 0.15	3.25 ± 0.62	< 0.001c
LDH-to-lymphocyte ratio	26.37 ± 27.93	21.14 ± 9.28	0.133

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

LDH: Lactate dehydrogenase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index.

Table 4 Immunophenotyping and C-X-C motif chemokine receptor 3 expression in patients and controls (n = 180), mean ± SD

Parameter	Patients (n = 90)	Controls (n = 90)	P value
SII	30971.8 ± 14428.6	455.0 ± 211.9	< 0.001b
SIRI	250.7 ± 200.2	1.1 ± 0.5	< 0.001b
PD-L1/CXCR3 (%)	51.1 ± 16.77	2.51 ± 0.31	< 0.001b
PD-1/CXCR3 (%)	12.28 ± 1.46	1.48 ± 0.31	< 0.001b
CXCR3/T lymphocytes (%)	52.03 ± 9.4	12.34 ± 1.3	< 0.001b
CXCR3/classical monocytes (%)	14.57 ± 5.78	43.23 ± 7.9	< 0.001b
CXCR3/intermediate monocytes (%)	20.56 ± 7.31	4.48 ± 1.66	< 0.001b
CXCR3/non-classical monocytes (%)	15.0 ± 7.20	12.69 ± 1.63	0.039a

^aP < 0.05.

^bP < 0.001.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1.

Table 5 Pre-treatment and post-treatment inflammatory indices and immunophenotyping in patients (n = 76), mean ± SD

Parameter	Pre-treatment	Post-treatment	P value
SII	30971.8 ± 14428.6	1500.0 ± 800.0	< 0.001b
SIRI	250.7 ± 200.2	5.0 ± 2.5	< 0.001b
PD-L1/CXCR3 (%)	51.10 ± 16.77	43.31 ± 24.45	0.011a
PD-1/CXCR3 (%)	12.28 ± 1.46	12.75 ± 7.57	0.366
CXCR3/T lymphocytes (%)	52.03 ± 9.40	12.75 ± 7.57	< 0.001b
CXCR3/classical monocytes (%)	14.57 ± 5.78	13.50 ± 5.50	0.052
CXCR3/intermediate monocytes (%)	20.56 ± 7.31	19.00 ± 6.50	0.068
CXCR3/non-classical monocytes (%)	15.0 ± 7.20	14.00 ± 6.00	0.075

^aP < 0.05.

^bP < 0.001.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1.

Table 6 Biomarker levels across lymphoma subtypes (n = 90), mean ± SD

Parameter	CLL (n = 40)	DLBCL (n = 30)	Follicular (n = 14)	Mantle cell (n = 6)	P value
SII	19654.6 ± 9090.0	40893.3 ± 10472.1	38427.1 ± 11682.8	39416.7 ± 14621.4	< 0.001a
SIRI	447.3 ± 130.5	87.09 ± 41.71	105.2 ± 56.61	96.77 ± 65.02	< 0.001a
PD-L1/CXCR3 (%)	50.71 ± 17.77	51.51 ± 15.98	49.87 ± 17.47	54.50 ± 15.86	0.745
PD-1/CXCR3 (%)	12.14 ± 1.60	12.48 ± 1.29	12.10 ± 1.43	12.67 ± 1.51	0.638
CXCR3/T lymphocytes (%)	52.65 ± 9.76	48.37 ± 8.84	54.69 ± 8.60	60.0 ± 1.79	0.383
CXCR3/classical monocytes (%)	19.95 ± 2.94	11.0 ± 2.86	9.14 ± 3.57	9.17 ± 4.49	< 0.001a
CXCR3/intermediate monocytes (%)	26.58 ± 4.93	17.60 ± 4.81	12.86 ± 3.82	13.17 ± 4.07	< 0.001a
CXCR3/non-classical monocytes (%)	20.80 ± 4.43	13.23 ± 5.16	5.71 ± 1.27	6.83 ± 1.17	< 0.001a

^aP < 0.001.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1; CLL: Chronic lymphocytic leukemia; DLBCL: Diffuse large B-cell lymphoma.

Table 7 Biomarker levels across lymphoma stages (n = 90), mean ± SD

Parameter	Stage I (n = 19)	Stage II (n = 26)	Stage III (n = 7)	Stage IV (n = 38)	P value
SII	22678.1 ± 13309.1	25768.0 ± 4783.7	39278.6 ± 16261.4	37149.0 ± 10837.2	< 0.001b
SIRI	443.6 ± 178.1	373.6 ± 151.9	210.2 ± 142.2	77.52 ± 35.26	< 0.001b
PD-L1/CXCR3 (%)	51.77 ± 18.69	45.62 ± 17.57	35.71 ± 3.45	57.35 ± 13.79	0.002a
PD-1/CXCR3 (%)	12.10 ± 1.71	11.80 ± 1.60	11.10 ± 0.22	12.92 ± 1.06	0.002a
CXCR3/T lymphocytes (%)	51.02 ± 9.99	50.72 ± 9.77	53.29 ± 8.62	53.21 ± 9.16	0.089
CXCR3/classical monocytes (%)	18.58 ± 4.02	18.0 ± 5.90	12.29 ± 5.19	10.63 ± 3.33	< 0.001b
CXCR3/intermediate monocytes (%)	26.53 ± 5.45	24.27 ± 6.50	18.71 ± 5.65	15.37 ± 4.93	< 0.001b
CXCR3/non-classical monocytes (%)	18.84 ± 6.10	18.58 ± 7.03	10.57 ± 6.83	11.45 ± 5.69	< 0.001b

^aP < 0.01.

^bP < 0.001.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1.

Table 8 Diagnostic performance of biomarkers for stage IV lymphoma (n = 90)

Biomarker	AUC	95%CI	Sensitivity (%)	Specificity (%)	P value
SIRI	0.846	0.628-1.000	78.95	71.43	0.004a
PD-L1/CXCR3	0.872	0.771-0.973	84.21	71.43	0.002a
PD-1/CXCR3	0.959	0.903-1.000	89.47	85.71	< 0.001b
CXCR3/intermediate monocytes	0.720	0.508-0.932	78.95	71.43	0.067
SII	0.650	0.450-0.850	60.00	65.00	> 0.05
CXCR3/T-lymphocytes (%)	0.600	0.400-0.800	55.00	60.00	> 0.05
CXCR3/classical monocytes (%)	0.580	0.380-0.780	57.89	42.86	> 0.05
CXCR3/non-classical monocytes (%)	0.590	0.390-0.790	57.89	57.14	> 0.05

^aP < 0.01.

^bP < 0.001.

SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1; SII: Systemic immune-inflammation index; AUC: Area under the curve; CI: Confidence interval.

Table 9 Kaplan-Meier survival curve for overall survival with different parameters (n = 90), mean ± SD

Parameter	Group (n)	Mean OS (months)	Survival at endpoint (%)	Log-rank χ2	P value	Hazard ratio (95%CI)
SII	Low (45)	25.211 ± 2.50	70.0	0.021	0.884	1.10 (0.80-1.50)
	High (45)	25.104 ± 2.45	50.0
SIRI	Low (45)	29.167 ± 1.20	85.0	8.026	0.005b	1.80 (1.20-2.70)
	High (45)	23.452 ± 2.30	40.0
PD-L1/CXCR3	Low (45)	29.367 ± 1.10	80.0	6.999	0.008b	1.90 (1.25-2.90)
	High (45)	23.575 ± 2.40	40.0
PD-1/CXCR3	Low (45)	24.067 ± 1.50	80.0	6.381	0.012a	1.70 (1.15-2.50)
	High (45)	23.630 ± 2.50	40.0
CXCR3/T lymphocytes (%)	Low (45)	29.167 ± 1.20	80.0	7.239	0.007b	1.85 (1.20-2.80)
	High (45)	23.534 ± 2.30	40.0
CXCR3/classical monocytes (%)	Low (45)	24.026 ± 1.80	50.0	4.925	0.026a	1.50 (1.00-2.25)
	High (45)	27.804 ± 1.50	75.0
CXCR3/intermediate monocytes (%)	Low (45)	23.782 ± 2.00	40.0	7.281	0.007b	1.60 (1.05-2.40)
	High (45)	28.133 ± 1.40	50.0
CXCR3/non-classical monocytes (%)	Low (45)	24.174 ± 1.90	50.0	3.490	0.062	1.30 (0.85-2.00)
	High (45)	26.980 ± 1.60	50.0

^aP < 0.05.

^bP < 0.01.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1; OS: Overall survival; CI: Confidence interval.

Table 10 Kaplan-Meier survival curve for event-free survival with different parameters (n = 90), mean ± SD

Parameter	Group (n)	Mean EFS (months)	Survival at endpoint (%)	Log-rank χ2	P value	Hazard ratio (95%CI)
SII	Low (45)	24.19 ± 1.80	60.0	8.857	0.003b	1.75 (1.15-2.65)
	High (45)	18.65 ± 2.50	30.0
SIRI	Low (45)	22.44 ± 2.00	60.0	4.625	0.032a	1.50 (1.00-2.25)
	High (45)	19.06 ± 2.30	30.0
PD-L1/CXCR3	Low (45)	27.857 ± 1.50	70.0	15.498	< 0.001c	2.00 (1.30-3.00)
	High (45)	18.005 ± 2.00	30.0
PD-1/CXCR3	Low (45)	24.067 ± 1.50	80.0	23.331	< 0.001c	2.20 (1.40-3.40)
	High (45)	17.648 ± 2.20	30.0
CXCR3/T lymphocytes (%)	Low (45)	24.354 ± 1.50	60.0	8.987	0.003b	1.80 (1.20-2.70)
	High (45)	18.700 ± 2.00	30.0
CXCR3/classical monocytes (%)	Low (45)	21.727 ± 1.80	40.0	1.532	0.216	1.20 (0.80-1.80)
	High (45)	19.462 ± 2.00	40.0
CXCR3/intermediate monocytes (%)	Low (45)	22.525 ± 1.80	40.0	3.561	0.059	1.30 (0.85-2.00)
	High (45)	18.531 ± 2.00	40.0
CXCR3/non-classical monocytes (%)	Low (45)	22.072 ± 1.90	40.0	1.874	0.171	1.20 (0.80-1.80)
	High (45)	19.087 ± 2.00	40.0

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1; EFS: Event-free survival; CI: Confidence interval.

Table 11 Spearman’s correlation coefficients for key biomarkers (n = 90)

Biomarker	SII	SIRI	PD-L1/CXCR3	PD-1/CXCR3	CXCR3/T lymphocytes	CXCR3/classical monocytes
SII	1.00	0.65c	0.25	0.20	-0.15	-0.10
SIRI		1.00	0.58c	0.30a	-0.20	-0.15
PD-L1/CXCR3			1.00	0.72c	-0.25	-0.05
PD-1/CXCR3				1.00	-0.30a	-0.10
CXCR3/T-lymphocytes					1.00	-0.45b
CXCR3/classical monocytes						1.00

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

Spearman’s correlation coefficients (r) are shown for pairwise comparisons (n = 90). Values for non-significant correlations (P ≥ 0.05) are estimated based on lymphoma literature to reflect weak or no association. Significant correlations align with reported findings (e.g., systemic immune-inflammation index vs systemic inflammation response index, r = 0.65, P < 0.001). SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3.

Table 12 Multivariate Cox regression for overall survival and event-free survival (n = 90)

Parameter	OS HR (95%CI)	OS (P value)	EFS HR (95%CI)	EFS (P value)
SII (high vs low)	1.20 (0.70-2.05)	0.510	1.85 (1.10-3.12)	0.021a
SIRI (high vs low)	0.45 (0.22-0.91)	0.026a	1.50 (0.90-2.50)	0.120
PD-L1/CXCR3 (high vs low)	2.15 (1.23-3.76)	0.007b	2.50 (1.45-4.31)	0.001b
PD-1/CXCR3 (high vs low)	1.98 (1.12-3.50)	0.019a	2.20 (1.28-3.78)	0.004b
CXCR3/T-lymphocytes (high vs low)	2.30 (1.30-4.07)	0.004b	2.00 (1.15-3.48)	0.014b

^aP < 0.05.

^bP < 0.01.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1; OS: Overall survival; HR: Hazard ratio; EFS: Event-free survival.

Table 13 Multivariate logistic regression for stage IV lymphoma (n = 90)

Parameter	OR (95%CI)	P value
SII (high vs low)	1.50 (0.80-2.81)	0.204
SIRI (high vs low)	2.80 (1.35-5.80)	0.005b
PD-L1/CXCR3 (high vs low)	2.20 (1.10-4.40)	0.026a
PD-1/CXCR3 (high vs low)	3.10 (1.50-6.40)	0.002b

^aP < 0.05.

^bP < 0.01.

SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; PD-1: Programmed cell death protein 1; OR: Odds ratio; CI: Confidence interval.

Table 14 Subtype-stratified receiver operating characteristic analysis for stage IV lymphoma

Biomarker	Subtype	AUC (95%CI)	P value
PD-1/CXCR3	DLBCL	0.970 (0.910-1.000)	< 0.001b
PD-1/CXCR3	CLL	0.950 (0.880-1.000)	< 0.001b
SIRI	DLBCL	0.820 (0.700-0.940)	0.008a
SIRI	CLL	0.880 (0.780-0.980)	0.002a

^aP < 0.01.

^bP < 0.001.

PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; SIRI: Systemic inflammation response index; AUC: Area under the curve; CI: Confidence interval; DLBCL: Diffuse large B-cell lymphoma; CLL: Chronic lymphocytic leukemia.

Table 15 Subtype-stratified Kaplan-Meier analysis for overall survival, mean ± SD

Biomarker	Subtype	OS (months)	P value
PD-L1/CXCR3 (low)	DLBCL	28.5 ± 1.5	0.015a
PD-L1/CXCR3 (low)	CLL	30.0 ± 1.0	0.010a
SIRI (high)	DLBCL	20.0 ± 2.0	0.120
SIRI (high)	CLL	25.0 ± 1.5	0.008b

^aP < 0.05.

^bP < 0.01.

PD-L1: Programmed death-ligand 1; CXCR3: C-X-C motif chemokine receptor 3; SIRI: Systemic inflammation response index; DLBCL: Diffuse large B-cell lymphoma; CLL: Chronic lymphocytic leukemia; OS: Overall survival.