Depressed and anxious mood and T-cell cytokine expressing populations in ovarian cancer patients

Abstract

The adaptive immune response of ovarian cancer patients has been linked to survival, and is known to be impaired in the tumor microenvironment. Little is known about relationships between biobehavioral factors such as depressed mood and anxiety and the adaptive immune response in ovarian cancer. Thirty-seven patients with epithelial ovarian cancer and 14 patients with benign ovarian neoplasms completed psychosocial questionnaires pre-surgery. Lymphocytes from peripheral blood, tumor, and ascites (fluid around the tumor), were obtained on the day of surgery. Expression of the Type-1 cytokine interferon-gamma (IFN gamma), and the Type-2 cytokine interleukin-4 (IL-4) by T-helper (CD4(+)) and T-cytotoxic (CD8(+)) cells was measured under autologous tumor-stimulated, polyclonally-stimulated, or unstimulated conditions. Links with mood were examined. Among cancer patients, marked elevations in unstimulated and tumor-stimulated Type-2 responses were seen, particularly in ascites and tumor-infiltrating lymphocytes (P values<0.01). With polyclonal stimulation, lymphocytes from all compartments expressed elevated Type-1 cytokines (P values<0.014). Depressed and anxious mood were both associated with significantly lower ratios of polyclonally-stimulated CD4(+) cells producing IFN gamma (TH(1) cells) vs. IL-4 (TH(2) cells) in all compartments (depressed mood: P=0.012; anxiety: P=0.038) and depressed mood was also related to lower ratios of polyclonally-stimulated CD8(+) cells producing IFN gamma (TC(1)) vs. IL-4 (TC(2)) (P=0.035). Although effects of polyclonal stimulation should be generalized with caution to the in vivo immune response, findings suggest that depressed and anxious mood are associated with greater impairment of adaptive immunity in peripheral blood and in the tumor microenvironment among ovarian cancer patients.

Figure 1

A) Comparisons of unstimulated TH₁ and TH₂ cells between compartments. For TH₁ cells, all between compartment P values > 0.28. For TH₂ cells, ascites vs. PBMC (P = 0.024) TIL vs. PBMC (P = 0.0003). Columns: mean, bars: SE. Y-axis in each panel expressed as percent positive cells in the CD3⁺ population. B) Comparisons of tumor-stimulated TH₁ vs. TH₂ cells between the 3 compartments. For TH₁ cells all between compartment P values > 0.49. For TH₂ cells, ascites vs. PBMC (P = 0.001), TIL vs. PBMC (P = 0.0006). C) Comparisons of P/I-stimulated TH₁ and TH₂ cells between the 3 compartments. No significant differences seen between compartments for either TH₁ or TH₂ cells (all P values > 0.41).

Figure 1

A) Comparisons of unstimulated TH₁ and TH₂ cells between compartments. For TH₁ cells, all between compartment P values > 0.28. For TH₂ cells, ascites vs. PBMC (P = 0.024) TIL vs. PBMC (P = 0.0003). Columns: mean, bars: SE. Y-axis in each panel expressed as percent positive cells in the CD3⁺ population. B) Comparisons of tumor-stimulated TH₁ vs. TH₂ cells between the 3 compartments. For TH₁ cells all between compartment P values > 0.49. For TH₂ cells, ascites vs. PBMC (P = 0.001), TIL vs. PBMC (P = 0.0006). C) Comparisons of P/I-stimulated TH₁ and TH₂ cells between the 3 compartments. No significant differences seen between compartments for either TH₁ or TH₂ cells (all P values > 0.41).

Figure 1

A) Comparisons of unstimulated TH₁ and TH₂ cells between compartments. For TH₁ cells, all between compartment P values > 0.28. For TH₂ cells, ascites vs. PBMC (P = 0.024) TIL vs. PBMC (P = 0.0003). Columns: mean, bars: SE. Y-axis in each panel expressed as percent positive cells in the CD3⁺ population. B) Comparisons of tumor-stimulated TH₁ vs. TH₂ cells between the 3 compartments. For TH₁ cells all between compartment P values > 0.49. For TH₂ cells, ascites vs. PBMC (P = 0.001), TIL vs. PBMC (P = 0.0006). C) Comparisons of P/I-stimulated TH₁ and TH₂ cells between the 3 compartments. No significant differences seen between compartments for either TH₁ or TH₂ cells (all P values > 0.41).

Figure 2

A) Comparisons of unstimulated TC₁ and TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.07), TIL vs. PBMC (P = 0.001). For TC₂ cells: ascites vs. PBMC (P = 0.005), TIL vs. PBMC (P < 0.0001). Columns: mean, bars: SE. Y-axis in each panel expressed as percent positive cells in the CD3⁺ population. B) Comparisons of tumor-stimulated TC₁ vs. TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.001), TIL vs. ascites (P = 0.06). For TC₂ cells: ascites vs. PBMC (P = 0.011), TIL vs. PBMC (P < 0.0001), TIL vs. ascites (P = 0.017). C) Comparisons of P/I-stimulated TC₁ and TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.013), TIL vs. PBMC (P = 0.039).

Figure 2

A) Comparisons of unstimulated TC₁ and TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.07), TIL vs. PBMC (P = 0.001). For TC₂ cells: ascites vs. PBMC (P = 0.005), TIL vs. PBMC (P < 0.0001). Columns: mean, bars: SE. Y-axis in each panel expressed as percent positive cells in the CD3⁺ population. B) Comparisons of tumor-stimulated TC₁ vs. TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.001), TIL vs. ascites (P = 0.06). For TC₂ cells: ascites vs. PBMC (P = 0.011), TIL vs. PBMC (P < 0.0001), TIL vs. ascites (P = 0.017). C) Comparisons of P/I-stimulated TC₁ and TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.013), TIL vs. PBMC (P = 0.039).

Figure 2

A) Comparisons of unstimulated TC₁ and TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.07), TIL vs. PBMC (P = 0.001). For TC₂ cells: ascites vs. PBMC (P = 0.005), TIL vs. PBMC (P < 0.0001). Columns: mean, bars: SE. Y-axis in each panel expressed as percent positive cells in the CD3⁺ population. B) Comparisons of tumor-stimulated TC₁ vs. TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.001), TIL vs. ascites (P = 0.06). For TC₂ cells: ascites vs. PBMC (P = 0.011), TIL vs. PBMC (P < 0.0001), TIL vs. ascites (P = 0.017). C) Comparisons of P/I-stimulated TC₁ and TC₂ cells between compartments. For TC₁ cells: ascites vs. PBMC (P = 0.013), TIL vs. PBMC (P = 0.039).

Figure 3

POMS depressed mood and TH₁/TH₂ ratio (natural log) in P/I-stimulated, tumor-stimulated, and unstimulated T-lymphocytes. Shown are fitted lines representing the slope of these relationships. (P < 0.012 for P/I-stimulated cells). Lines are fitted representing Stage III ovarian cancer and PBMC.