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Tumor mica status predicts the efficacy of immunotherapy with cytokine-induced killer cells for patients with gastric cancer

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Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P61

https://doi.org/10.1186/2051-1426-3-S2-P61

  • Published:

Keywords

  • Gastric Cancer
  • Current Standard Treatment
  • Mica Status
  • Gastric Cancer Tumor
  • Clinical Trial Cohort

Background

Accumulating evidence has demonstrated that cytokine-induced killer (CIK) cell immunotherapy may improve outcomes when used as an adjuvant to current standard treatment. Previous studies showed that cell signaling through MHC I-related Chain A (MICA)-Natural killer group 2, member D (NKG2D) results in CIK cells activation leading to cytolytic activities against tumor cells. In this study, we determine the relationship between the expression of MICA in gastric cancer tumors after D2 gastrectomy and the clinical outcome of a CIK containing adjuvant therapy.

Methods

From January 2009 to March 2012, ninety-five consecutive patients with gastric cancer after D2 gastrectomy who received adjuvant chemotherapy combined with CIK cell therapy were enrolled (Table 1). The MICA expression of their tumors was determined by immunohistochemistry (IHC). The IHC score of was obtained by adding the intensity and percentage scores.

Table 1

Variable

 

N

m DFS

p-value

m OS

p-value

Sex

Male

66

42.0

0.373

44.0

0.229

 

Female

29

42.0

 

50.0

 

Age

<65

67

41.0

0.588

48.0

0.464

 

≥65

28

43.0

 

43.0

 

Histological grade

G1-G2

48

43.0

0.480

48.0

0.556

 

G3-G4

47

31.0

 

43.0

 

Stage

II

44

50.0

0.001

51.0

0.006

 

III

51

36.0

 

41.0

 

Adjuvant Chemotherapy

Xelox, Folfox4

57

41.0

0.250

43.0

0.257

 

PF

38

42.0

 

46.0

 

CIK cycles

<5

54

40.0

0.046

42.0

0.075

 

≥5

41

48.0

 

50.0

 

MICA status

High

38

46.0

0.027

48.0

0.031

 

Low

57

41.0

 

42.0

 

Results

The MICA protein was detected mainly at the cell membrane and in the cytoplasm (Fig.1). High-expression of MICA protein, with IHC scores of 5-7, was documented in 38 of 95 tumor samples (40.0%). The MICA status was significantly association with the age and stage, p=0.008 and p=0.023, respectively (Table 2). Phenotypic analysis of NKG2D on in vitro expanded CIK cells showed that the percentage of NKG2D+ in CD3+/CD56+, CD3-/CD56+, and CD3+/CD8+ cells populations were 97.2±1.4%, 97.9±1.8%, and 95.6±2.1%, respectively. For the 95 patients, the median DFS was 42.0 months, 95% CI = 40.82-43.18 months, and median OS was 45.0 months, 95% CI = 41.82-48.18 months, the 3-year and 4-year DFS rates were 70.5% and 34.7%, respectively, and the 3-year and 4-year OS rates were 82.1% and 49.5%, respectively (Fig. 2A). For patient with high MICA expressing tumors the median DFS and OS were longer than for the patients with tumors with low expression of MICA; 46.0 months vs. 41.0 months (p=0.027), and 48.0 months vs. 42.0 months (p=0.031), respectively(Fig. 2B, Table 3). In a multivariate analysis, stage and MICA expression were independent prognostic factors for DFS and OS (Table 4).

Table 2

Characteristics

 

Total95

MICA highN=38

MICA lowN=57

p-value

Sex

Male

66

25

41

0.524

 

Female

29

13

16

 

Age

<65

67

21

46

0.008

 

≥65

28

17

11

 

Histological grade

G1-G2

48

23

25

0.111

 

G3-G4

47

15

32

 

Stage

II

44

23

21

0.023

 

III

51

15

36

 

Adjuvant Chemotherapy

Xelox, Folfox4

57

25

32

0.347

 

PF

38

13

25

 

CIK cycles

<5

54

18

36

0.128

 

≥5

41

20

21

 

Table 3

Characteristics

 

Number

Constituent ratio

Sex

Male

66

69.5%

 

Female

29

30.5%

Age

<65

67

70.5%

 

≥65

28

29.5%

Histological grade

G1-G2

48

50.5%

 

G3-G4

47

49.5%

Stage

II

44

46.3%

 

III

51

53.7%

Adjuvant Chemotherapy

Xelox, Folfox4

57

60.0%

 

PF

38

40.0%

CIK cycles

<5

54

56.9%

 

≥5

41

43.2%

Table 4

Variable

DFS

  

OS

  
 

P value

Hazard ratio

95%Ci

P value

Hazard ratio

95%Ci

Stage

0.001

1.915

1.270-2.886

0.010

1.713

1.138-2.577

MICA

0.035

1.578

1.033-2.409

0.040

1.557

1.020-2.376

Conclusion

Our findings show that adjuvant chemotherapy plus CIK therapy treatment is a promising modality for treating gastric cancer patients after D2 gastrectomy. Especially, those who have tumors with high-expression of MICA were more likely to benefit from such a treatment strategy. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.

Authors’ Affiliations

(1)
Fujian Provincial Cancer Hospital, Fuzhou, China

Copyright

© Chen et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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