Neutrophil extracellular traps predict sensitivity to neoadjuvant chemotherapy combined with immunotherapy in locally advanced gastric cancer

Table 1 Baseline characteristics of locally advanced gastric cancer patients before neoadjuvant chemotherapy combined with immunotherapy treatment, n (%)

Characteristics	Total (n = 31)	High-NETs (n = 16)	Low-NETs (n = 15)	P value
Sex				0.537
Female	11 (35)	7 (44)	4 (27)
Male	20 (65)	9 (56)	11 (73)
Age				0.378
< 65	18 (58)	11 (69)	7 (47)
≥ 65	13 (42)	5 (31)	8 (53)
Location				0.426
Lower third	9 (29)	5 (31)	4 (27)
Middle third	15 (48)	9 (56)	6 (40)
Upper third	7 (23)	2 (12)	5 (33)
cT				0.505
cT3	7 (23)	4 (25)	3 (20)
cT4a	7 (23)	5 (31)	2 (13)
cT4b	17 (55)	7 (44)	10 (67)
cN				0.014
cN1	1 (3)	1 (6)	0 (0)
cN2	11 (35)	2 (12)	9 (60)
cN3	19 (61)	13 (81)	6 (40)
Tumor grade				0.34
G1	1 (3)	0 (0)	1 (7)
G2	10 (32)	4 (25)	6 (40)
G3	20 (65)	12 (75)	8 (53)
PD-L1 scores, median (Q1, Q3)	7 (2.5, 9.5)	3.5 (1, 7)	9 (5, 16)	0.004
NLR, mean ± SD	3 ± 1.38	3.16 ± 1.53	2.84 ± 1.24	0.532
PD1				0.131
Nivolumab	15 (48)	5 (31)	10 (67)
Tislelizumab	12 (39)	8 (50)	4 (27)
Camrelizumab	1 (3)	1 (6)	0 (0)
Penpulimab	1 (3)	1 (6)	0 (0)
Toripalimab	1 (3)	1 (6)	0 (0)
Zimberelimab	1 (3)	0 (0)	1 (7)
Chemotherapy				0.484
Paclitaxel	2 (6)	2 (12)	0 (0)
SOX	29 (94)	14 (88)	15 (100)

NET: Neutrophil extracellular traps; NLR: Neutrophil-to-lymphocyte ratio; SOX: S-1 (tegafur) and oxaliplatin.

Table 2 Pre-neoadjuvant chemotherapy combined with immunotherapy neutrophil extracellular traps density correlates with treatment response in locally advanced gastric cancer patients receiving neoadjuvant chemotherapy combined with immunotherapy, n (%)

Characteristics	High NETs (n = 16)	Low NETs (n = 15)	P value
pCR			0.037
no-pCR	15 (94)	9 (60)
pCR	1 (6)	6 (40)
Respond			0.023
No	14 (88)	7 (47)
Yes	2 (12)	8 (53)

NET: Neutrophil extracellular traps; pCR: Pathological complete response.

Table 3 Logistic regression analysis for predictors of pathological complete response in locally advanced gastric cancer patients receiving neoadjuvant chemotherapy combined with immunotherapy

Variables	Univariate analyses		Multivariate analyses
	HR (95%CI)	P value	HR (95%CI)	P value
Sex
Female	1 [Reference]	NA
Male	1.50 (0.27-8.38)	0.644
Age
< 65	1 [Reference]	NA
≥ 65	2.12 (0.34-13.13)	0.421
Tumor location
Lower third	1 [Reference]	NA
Middle third	5.20 (0.71-37.90)	0.104
Upper third	4.80 (0.40-58.01)	0.217
cT stage
cT3	1 [Reference]	NA
cT4a	1.00 (0.05-19.96)	1.000
cT4b	0.40 (0.04-4.24)	0.447
cN stage
cN1	1 [Reference]	NA
cN2	0.00 (0.00-Inf)	0.995
cN3	0.00 (0.00-Inf)	0.995
PD-L1 scores	0.87 (0.77-0.99)	0.028	0.85 (0.73-0.99)	0.041
Tumor grade
G1-2	1 [Reference]	NA
G3	1.50 (0.27-8.38)	0.644
Immunotherapy
Nivolumab	1 [Reference]	NA
Tislelizumab	1.82 (0.27-12.17)	0.538
Others	1.09 (0.09-13.78)	0.946
NLR
High	1 [Reference]	NA
Low	0.33 (0.03-3.26)	0.345
Pre-NACI NET
High	1 [Reference]	NA	1 [Reference]	NA
Low	0.10 (0.01-0.97)	0.047	0.07 (0.00-0.96)	0.047

NACI: Neoadjuvant chemotherapy combined with immunotherapy; HR: Hazard ratio; CI: Confidence interval; NET: Neutrophil extracellular trap; NLR: Neutrophil-to-lymphocyte ratio.