Human Leukocyte Antigen Class I, MHC Class I Chain-Related Molecule A, and CD8+/Regulatory T-Cell Ratio: Which Variable Determines Survival of Cervical Cancer Patients?

DOI: 10.1158/1078-0432.CCR-07-4554 Published April 2008

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Fig. 1.
Quadruple and enzymatic immunohistochemical staining of TIL. A, normal cervical epithelium. Black, silver-stained keratinocytes. The different TILs enumerated are CD3⁺CD8⁺CD57⁻ T cells (purple), CD3⁺CD8⁻ T cells (red), CD3⁺CD8⁺CD57⁺ cells (white), CD8⁺CD57⁺ cells (blue green), CD3⁺CD57⁺ cells (yellow), and CD57⁺ cells (green). B, cervical cancer sample with a robust intraepithelial and stromal infiltrate pattern. C, cervical cancer sample with low numbers of TIL. D, cervical cancer sample with a high number of FoxP3⁺ Treg (brown nuclear staining). E, cervical cancer sample with low numbers of FoxP3⁺ Treg.
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Fig. 2.
Immunohistochemical staining of ligands in cervical cancer samples. A, HLA-A–negative tumor. Notice the normal staining in the stroma. B, weak HLA-A staining. C, normal pattern of HLA-A staining. D, fluorescent immunostaining showing normal MICA expression. E, weak MICA staining.
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Fig. 3.
Kaplan-Meier curves and log-rank test results of variables significantly associated with overall 5-y survival. A, Treg. B, CD8⁺/Treg ratio. C, HLA-A expression. D, HLA-A expression stratified for MICA expression. E, HLA-A and MICA expression stratified for CD8⁺/Treg ratio.

Table 1.

Clinicopathologic variables

Abbreviations: FIGO, International Federation of Gynecologists and Obstetricians; SCC, squamous cell carcinoma; ADC, adenocarcinoma; ADSC, adenosquamous carcinoma.

Table 2.

ieTIL subtypes in normal cervix and cervical cancers

Table 3.

Univariate and multivariate Cox analysis of ieTIL subtypes, HLA-A, MICA, and clinicopathologic variables

Variable			HR (95% CI)
Univariate Cox analysis
Lymph node status	Positive vs negative	6.44 (2.79-14.82)	0.001
Tumor size (mm)	≥40 vs <40	7.77 (2.85-21.16)	0.001
Vasoinvasion	Positive vs negative	3.11 (1.36-7.11)	0.007
Infiltration depth (mm)	≥15 vs <15	4.56 (1.80-11.60)	0.001
Treg	High vs low number	2.76 (1.01-7.55)	0.048
CD8⁺/Treg ratio	Low vs high ratio	2.82 (1.09-7.27)	0.032
HLA-A	Weak vs strong expression	2.87 (1.04-7.95)	0.042
Multivariate Cox analysis: single variables
Lymph nodes	Positive vs negative	3.38 (1.16-9.83)	0.025
Tumor size (mm)	≥40 vs <40	5.39 (1.89-67.05)	0.002
Vasoinvasion	Positive vs negative	1.14 (0.42-3.08)	0.800
Infiltration depth (mm)	≥15 vs <15	2.69 (0.76-9.36)	0.126
CD8⁺/Treg ratio	Low vs high ratio	2.71 (1.01-7.26)	0.047
Treg*	High vs low number	2.25 (0.67-7.50)	0.187
HLA-A*	Weak vs strong expression	2.70 (0.90-8.12)	0.077
Multivariate Cox analysis: HLA-A + MICA
Lymph nodes		3.48 (1.15-10.52)	0.027
Tumor size		6.70 (2.38-18.91)	0.0003
Vasoinvasion		1.36 (0.52-3.59)	0.534
Infiltration depth		1.97 (0.64-6.08)	0.240
HLA-A + MICA	Weak expression vs rest	4.04 (1.61-10.13)	0.003
Multivariate Cox analysis: HLA-A + MICA + CD8⁺/Treg
Lymph nodes		2.15 (0.67-6.90)	0.199
Tumor size		6.21 (2.13-18.12)	0.001
Vasoinvasion		1.32 (0.48-3.62)	0.588
Infiltration depth		2.97 (0.80-11.04)	0.105
HLA-A + MICA + CD8⁺/Treg	Weak expression/low ratio vs rest	4.91 (1.82-13.22)	0.002

Abbreviation: 95% CI, 95% confidence interval.
↵* Variables were analyzed in separate multivariate analyses as not to influence each other's HR.