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The prognostic significance of tumor-immune microenvironment in ascites of patients with high-grade serous carcinoma

Simona Miceska
Simona Miceska
, 
Erik Skof
Erik Skof
, 
Simon Bucek
Simon Bucek
, 
Cvetka Grasic Kuhar
Cvetka Grasic Kuhar
, 
Gorana Gasljevic
Gorana Gasljevic
, 
Spela Smrkolj
Spela Smrkolj
 et 
Veronika Kloboves Prevodnik
Veronika Kloboves Prevodnik
   | 30 nov. 2023
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Article Category: Research Article
Publié en ligne: 30 nov. 2023
Pages: 493 - 506
Reçu: 27 juin 2023
Accepté: 13 août 2023
DOI: https://doi.org/10.2478/raon-2023-0046
Mots clés
© 2023 Simona Miceska et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1.

Gating strategy for immune cells in ascites. (A) CD3+ T cells were gated on CD45+. (B) The depicted gate shows CD4+ vs. CD8+ subsets gated on CD3+ T cells and (C) CD103 expression on CD8+. The same gating strategy was applied for CD103 expression on CD4+ (not shown). (D) Gating representative for Tregs. The dot plot depicts CD4+ cells discriminated according to CD127 and CD25 positivity. (E) NKT cells were gated according to CD3 and CD56 positivity. (F) NK cells were gated according to CD16 and CD56 positivity. Two subsets were defined: CD56brightCD16− and CD56dimCD16+. (G) The dot plot depicts macrophages according to CD14 and CD68 positivity (pre-gated on CD11b+CD45+ cells). (H) M1-like macrophages were defined as CD206− macrophages, and M2-like as CD206+ macrophages. (I) DCs were gated per exclusion − as lineage-negative cells (no expression of CD3/CD11b/CD14/CD16/CD19/CD20/CD34/CD56) and further discriminated by CD123 and HLA-DR positivity. (J) B cells were gated as CD19+ cells per CD45+. (K) PD-1 and PD-L1 positivity was detected on each cell population/subset.
Gating strategy for immune cells in ascites. (A) CD3+ T cells were gated on CD45+. (B) The depicted gate shows CD4+ vs. CD8+ subsets gated on CD3+ T cells and (C) CD103 expression on CD8+. The same gating strategy was applied for CD103 expression on CD4+ (not shown). (D) Gating representative for Tregs. The dot plot depicts CD4+ cells discriminated according to CD127 and CD25 positivity. (E) NKT cells were gated according to CD3 and CD56 positivity. (F) NK cells were gated according to CD16 and CD56 positivity. Two subsets were defined: CD56brightCD16− and CD56dimCD16+. (G) The dot plot depicts macrophages according to CD14 and CD68 positivity (pre-gated on CD11b+CD45+ cells). (H) M1-like macrophages were defined as CD206− macrophages, and M2-like as CD206+ macrophages. (I) DCs were gated per exclusion − as lineage-negative cells (no expression of CD3/CD11b/CD14/CD16/CD19/CD20/CD34/CD56) and further discriminated by CD123 and HLA-DR positivity. (J) B cells were gated as CD19+ cells per CD45+. (K) PD-1 and PD-L1 positivity was detected on each cell population/subset.

FIGURE 2.

Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) of high-grade serous carcinoma (HGSC) patients based on treatment characteristics.ns = non-significant
Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) of high-grade serous carcinoma (HGSC) patients based on treatment characteristics.ns = non-significant

FIGURE 3.

Box plots showing median (range) and quartiles for (A) T cells, NK cells, macrophages, DCs, B cells, and their subsets in the ascites of HGSC patients, and (B) the expression of PD-1 for each immune population/subset at disease presentation. CD3+ T cells, NKT cells, CD56brightCD16− and CD56dimCD16+ NK cells, macrophages, DCs, and B cells are given as a percentage per all CD45+ cells, while each subset is given as a percentage per its main population.
Box plots showing median (range) and quartiles for (A) T cells, NK cells, macrophages, DCs, B cells, and their subsets in the ascites of HGSC patients, and (B) the expression of PD-1 for each immune population/subset at disease presentation. CD3+ T cells, NKT cells, CD56brightCD16− and CD56dimCD16+ NK cells, macrophages, DCs, and B cells are given as a percentage per all CD45+ cells, while each subset is given as a percentage per its main population.

FIGURE 4.

Box plots showing the median (range) and quartiles for the percentages of different immune cells at presentation and their association with surgery type (no surgery vs. primary vs. interval) the patients were later assigned with.
Box plots showing the median (range) and quartiles for the percentages of different immune cells at presentation and their association with surgery type (no surgery vs. primary vs. interval) the patients were later assigned with.

FIGURE 5.

Box plots showing the median (range) and quartiles for the percentages of different immune cells at presentation and their association with residual disease after surgery (less (no and ≤ 1cm) residual tumor vs. more (< 1 cm and inoperable) residual tumor).
Box plots showing the median (range) and quartiles for the percentages of different immune cells at presentation and their association with residual disease after surgery (less (no and ≤ 1cm) residual tumor vs. more (< 1 cm and inoperable) residual tumor).

FIGURE 6.

Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) of high-grade serous carcinoma (HGSC) patients. PFS curves show significant differences for patients stratified as having (A) low or high percentages of immune cells, (B) low or high expression of PD-1 on immune cells, OS curves show significant differences for patients stratified as having (C) low or high percentages of immune cells, (D) low or high expression of PD-1 on immune cells. Cut-off values were based on the population median. P-values for significant differences are given.
Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) of high-grade serous carcinoma (HGSC) patients. PFS curves show significant differences for patients stratified as having (A) low or high percentages of immune cells, (B) low or high expression of PD-1 on immune cells, OS curves show significant differences for patients stratified as having (C) low or high percentages of immune cells, (D) low or high expression of PD-1 on immune cells. Cut-off values were based on the population median. P-values for significant differences are given.

Univariate analysis of patient's survival based on treatment characteristics

Progression-free survival Overall survival
HR (95% Cl) P-value HR (95% Cl) P-value
Age at diagnosis (≤ 65 vs. > 65 years) 0.504 0.266–0.954 0.022 0.271 0.117–0.627 0.002
FIGO stage (III vs. IV) 1.331 0.691–2.566 0.381 0.312 0.112–0.872 0.026
Surgery < 0.001 < 0.001
  no vs. primary 3.365 1.248–9.072 0.002 9.907 3.045–32.23 < 0.001
  no vs. interval 2.981 1.133–7.845 0.001 8.529 2.270–32.05 < 0.001
  primary vs. interval 0.570 0.253–1.282 0.192 0.605 0.186–1.973 0.239
Residual disease after surgery < 0.0001 < 0.001
  no residual tumor vs. ≤ 1cm 0.764 0.314–1.858 0.538 0.189 0.045 –0.799 0.020
  no residual tumor vs. > 1cm 0.121 0.006–2.256 < 0.001 0.066 0.003–1.408 < 0.001
  residual tumor ≤ 1cm vs. > 1cm 0.131 0.008–2.209 < 0.001 0.131 0.009–1.988 < 0.001
Chemotherapy (adjuvant vs. neoadjuvant) 0.358 0.177–0.725 0.022 0.307 0.129–0.732 0.039
Bevacizumab (no/yes) 0.979 0.500–1.917 0.950 4.280 1.888–9.703 0.003
BRCA1/2 mutation (no vs. yes) 1.721 0.827–3.584 0.186 1.734 0.698–4.307 0.274
Olaparib (no vs. yes) 3.486 1.765–6.884 0.005 3.148 1.329–7.629 0.044

Multivariate analysis of the treatment characteristics and immune cells

Variables included in the multivariate analysis Progression-free survival Overall survival
HR (95% Cl) P-value HR (95% Cl) P-value
Primary surgery (no vs. yes) 0.640 0.194–2.114 0.509 0.592 0.101–3.454 0.560
Residual disease after surgery (no residual tumor and ≤ 1 cm of residual tumor vs. > 1 cm residual tumor) 0.408 0.169–0.983 0.046 0.009 0.001–0.092 < 0.001
CD103+CD3+ (low vs. high) 0.605 0.266–1.374 0.230 0.632 0.182–1.307 0.470
CD56brightCD16− NK cells (low vs. high) 1.707 0.683–4.265 0.252 NA NA NA
DCs (no vs. yes) 0.394 0.155–0.998 0.049 0.419 0.135–1.307 0.134
Macrophages (low vs. high) NA NA NA 0.592 0.101–3.545 0.560

Clinical characteristics of the patients included in the study

Age at diagnosis (years)
  Mean 64
  Range 41–84
FIGO stage (N, %)
  IIIB 1 (2)
  IIIC 34 (72)
  IVA 7 (15)
  IVB 5 (11)
Surgery (N, %)
  Primary 11 (23)
  Interval 23 (49)
  No surgery (remained inoperable) 13 (28)
Residual disease after surgery (N, %)
  No residual tumor 19 (40)
  Residual tumor ≤ 1 cm 12 (26)
  Residual tumor > 1 cm 3 (6)
Chemotherapy (N, %)
  Adjuvant 11 (23)
  Neoadjuvant* 36 (77)
Bevacizumab (N, %)
  No 31 (66)
  Yes 16 (34)
Positive family history (N, %)
  No 30 (64)
  Yes 17 (36)
BRCA1/2 mutation (N, %)
  No 31 (66)
  Yes 12 (26)
  Unknown 4 (9)
Olaparib (N, %)
  No 35 (74)
  Yes 12 (26)
Disease progression
  No 11 (23)
  Yes 36 (47)
Death
  No 24 (51)
  Yes 23 (49)

Univariate analysis of patient's survival based on the low/high percentages of immune cells in the ascites at disease presentation

Progression-free survival Overall survival
HR (95% Cl) P-value HR (95% Cl) P-value
CD3+ (low vs. high) 1.098 0.563–2.142 0.777 0.670 0.301–1.493 0.324
CD4+ (low vs. high) 0.547 0.260–1.150 0.110 0.401 0.174–0.928 0.038
CD8+ (low vs. high) 1.918 0.887–4.148 0.066 2.854 1.182–6.889 0.008
CD8/CD4 index (low vs. high) 1.076 0.560–2.069 0.820 2.973 1.304–6.780 0.010
Tregs (low vs. high) 0.856 0.412–1.778 0.677 0.807 0.324–2.006 0.649
CD103+CD3+ (low vs. high) 2.152 1.050–4.408 0.017 3.234 1.365–7.661 0.009
CD103+CD4+ (low vs. high) 0.515 0.232–1.147 0.108 0.816 0.328–2.031 0.661
CD103+CD8+ (low vs. high) 1.984 0.899–4.379 0.085 1.744 0.706–4.309 0.245
NKT cells (low vs. high) 0.520 0.246–1.101 0.060 1.208 0.507–2.878 0.661
CD56brightCD16− NK cells (low vs. high) 2.111 1.013–4.396 0.044 2.903 1.304–6.464 0.016
CD56dim16+ NK cells (low vs. high) 1.399 0.694–2.820 0.362 1.851 0.756–4.533 0.157
Macrophages (low vs. high) 0.601 0.245–1.478 0.275 1.943 0.754–5.006 0.008
M1-like macrophages (low vs. high) 0.868 0.224–3.370 0.835 1.562 0.321–7.604 0.533
M2-like macrophages (low vs. high) 2.142 0.553–8.297 0.224 2.854 1.182–6.889 0.080
B cells (low vs. high) 1.161 0.560–2.450 0.686 0.464 0.188–1.141 0.102
DCs (low vs. high) 2.245 0.799–6.310 0.042 3.307 0.939–11.65 0.007
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