Nomograms to Predict the Density of Tumor-Infiltrating Lymphocytes in Patients With High-Grade Serous Ovarian Cancer

Danian Dai, Lili Liu, He Huang, Shangqiu Chen, Bo Chen, Junya Cao, Xiaolin Luo, Feng Wang, Rongzhen Luo, Jihong Liu, Danian Dai, Lili Liu, He Huang, Shangqiu Chen, Bo Chen, Junya Cao, Xiaolin Luo, Feng Wang, Rongzhen Luo, Jihong Liu

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) have important roles in predicting tumor therapeutic responses and progression, however, the method of evaluating TILs is complicated. We attempted to explore the association of TILs with clinicopathological characteristics and blood indicators, and to develop nomograms to predict the density of TILs in patients with high-grade serous ovarian cancer (HGSOC).

Methods: The clinical profiles of 197 consecutive postoperative HGSOC patients were retrospectively analyzed. Tumor tissues and matched normal fallopian tubes were immunostained for CD3+, CD8+, and CD4+ T cells on corresponding tissue microarrays and the numbers of TILs were counted using the NIH ImageJ software. The patients were classified into low- or high-density groups for each marker (CD3, CD4, CD8). The associations of the investigated TILs to clinicopathological characteristics and blood indicators were assessed and the related predictors for densities of TILs were used to develop nomograms; which were then further evaluated using the C-index, receiver operating characteristic (ROC) curves and calibration plots.

Results: Menopausal status, estrogen receptor (ER), Ki-67 index, white blood cell (WBC), platelets (PLT), lactate dehydrogenase (LDH), and carbohydrate antigen 153 (CA153) had significant association with densities of tumor-infiltrating CD3+, CD8+, or CD4+ T cells. The calibration curves of the CD3+ (C-index = 0.748), CD8+ (C-index = 0.683) and CD4+ TILs nomogram (C-index = 0.759) demonstrated excellent agreement between predictions and actual observations. ROC curves of internal validation indicated good discrimination for the CD8+ TILs nomogram [area under the curve (AUC) = 0.659, 95% CI 0.582-0.736] and encouraging performance for the CD3+ (AUC= 0.708, 95% CI 0.636-0.781) and CD4+ TILs nomogram (AUC = 0.730, 95% CI 0.659-0.801).

Conclusion: Menopausal status, ER, Ki-67 index, WBC, PLT, LDH, and CA153 could reflect the densities of T cells in the tumor microenvironment. Novel nomograms are conducive to monitor the immune status of patients with HGSOC and help doctors to formulate the appropriate treatment strategies.

Keywords: blood indicators; high-grade serous ovarian cancer; nomograms; tumor microenvironment; tumor-infiltrating lymphocytes.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Dai, Liu, Huang, Chen, Chen, Cao, Luo, Wang, Luo and Liu.

Figures

Figure 1
Figure 1
Expression of CD3+, CD8+, and CD4+ TILs in HGSOC tissues (Tu) and matched normal epithelium of the fallopian tubes (N), shown at 40× magnification with inset (400×). (A–C) Representative images of CD3+, CD8+, and CD4+ TILs in the normal fallopian tube tissues. (D, G) Representative images of low-density and high-density of CD3+ TILs in the HGSOC tissues. (E, H) Representative images of low-density and high-density CD8+ TILs in the HGSOC tissues. (F, I) Representative images of low-density and high-density of CD4+ TILs in the HGSOC tissues. (J) Box plots of CD3+, CD8+, and CD4+ TILs per mm2 in tumor tissues (n=197) or normal epithelium of the fallopian tubes (n=173). Quantitative data are presented as mean ± SEM. TILs, tumor-infiltrating lymphocytes; HGSOC, high-grade serous ovarian cancer.
Figure 2
Figure 2
Immunohistochemical staining of H&E, ER, Ki-67, and p53 in HGSOC tissues (Tu) and matched normal fallopian tubes tissue (N), shown at 40× magnification with inset (400×). (A, B) Representative images of H&E in the matched normal epithelium of the fallopian tubes (N) and HGSOC tissues (Tu). (C, D) Representative images of negative and positive ER in HGSOC tissues are presented. (E, F) Representative images of high and low Ki-67 index in HGSOC tissues are shown (G, H) Representative images of mutant type and wild type p53 staining in HGSOC tissues are presented. TILs, tumor-infiltrating lymphocytes; HGSOC, high-grade serous ovarian cancer; H&E, Hematoxylin and Eosin.
Figure 3
Figure 3
Correlation between various blood indicators and the density of TILs. (A) The density of CD3+ TILs showed a positive correlation with the level of serum LDH, with a coefficient of 0.153 (p = 0.031). (B) The density of CD3+ TILs was negatively related to the PLT, with a coefficient of −0.186 (P = 0.009). (C) The density of CD3+ TILs showed a positive correlation the level of serum CA153, with a coefficient of 0.168 (P = 0.019). (D) The density of CD8+ TILs showed a tendency that positively correlated with the level of serum LDH, with a coefficient of 0.111 (P = 0.120). (E) The density of CD8+ TILs showed a tendency that positively related to the serum CA153, with a coefficient of 0.133 (P = 0.065). (F) The density of CD4+ TILs showed a tendency that negatively correlated with the number of WBC in the blood, with a coefficient of -0.126 (P = 0.079). (G) The density of CD4+ TILs was positively related to the CA153, with a coefficient of 0.207 (P = 0.004). TILs, tumor-infiltrating lymphocytes; WBC, white blood cells; LDH, lactate dehydrogenase; PLT, platelet; CA153, carbohydrate antigen 153.
Figure 4
Figure 4
Nomograms, calibration curves, and ROC curves analysis for predicting density of TILs in patients with high-grade serous ovarian cancer. (A) The CD3+ TILs prediction nomogram. (B) Calibration curves for predicting density of CD3+ TILs. (C) ROC curves of CD3+ TILs prediction nomogram in the internal testing set. (D) The CD8+ TILs prediction nomogram. (E) Calibration curves for predicting density of CD8+ TILs. (F) ROC curves of CD8+ TILs prediction nomogram in the internal testing set. (G) The CD4+ TILs prediction nomogram. (H) Calibration curves for predicting density of CD4+ TILs. (I) ROC curves of CD4+ TILs prediction nomogram in the internal testing set. All the points assigned on the top point scale for each factor are summed together to generate a total point score. The total point score is projected on the bottom scales to determine the probability of high density for tumor-infiltrating T cells in an individual. The nomogram-predicted frequency of high T cell density is plotted on the x-axis, and the actual observed frequency of high T cell density is plotted on the y-axis. The AUC was calculated, and its 95% CI was estimated by bootstrapping. TILs, tumor-infiltrating lymphocytes; ROC, receiver operating characteristic; 95% CI, 95% confidence interval.

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