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The prognostic significance of programmed cell death protein 1 and its ligand on lymphoma cells and tumor-immune cells in diffuse large B-cell lymphoma, not otherwise specified

Teja Cas Slak
Teja Cas Slak
, 
Simona Miceska
Simona Miceska
, 
Gorana Gasljevic
Gorana Gasljevic
, 
Lucka Boltezar
Lucka Boltezar
 e 
Veronika Kloboves-Prevodnik
Veronika Kloboves-Prevodnik
   | 21 feb 2024
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Article Category: Research Article
Pubblicato online: 21 feb 2024
Pagine: 99 - 109
Ricevuto: 07 nov 2023
Accettato: 25 nov 2023
DOI: https://doi.org/10.2478/raon-2024-0010
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© 2024 Teja Cas Slak et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1.

Representable images of the double immunohistochemical staining for (A) PD-1/PAX5 and (B) PD-L1/PAX5. Red chromogen indicates PAX5 in DLBCL, NOS nuclei of LCs, with brown chromogen is labeled PD-1 (A) or PD-L1 (B), respectively (40x magnification).DLBCL = diffuse large B-cell lymphoma; LCs = lymphoma cells; NOS = not otherwise specified; PD-1 = programmed cell death protein 1; PD-L1 = PD-1 ligand
Representable images of the double immunohistochemical staining for (A) PD-1/PAX5 and (B) PD-L1/PAX5. Red chromogen indicates PAX5 in DLBCL, NOS nuclei of LCs, with brown chromogen is labeled PD-1 (A) or PD-L1 (B), respectively (40x magnification).DLBCL = diffuse large B-cell lymphoma; LCs = lymphoma cells; NOS = not otherwise specified; PD-1 = programmed cell death protein 1; PD-L1 = PD-1 ligand

FIGURE 2.

Kaplan-Meier curves for (A) progression-free survival and (B) overall survival, representing only significant differences among all analyzed clinicopathological characteristics of diffuse large B-cell lymphoma, not otherwise specified patients.
Kaplan-Meier curves for (A) progression-free survival and (B) overall survival, representing only significant differences among all analyzed clinicopathological characteristics of diffuse large B-cell lymphoma, not otherwise specified patients.

FIGURE 3.

Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) for PD-1 and PD-L1 on tumor-immune cells. The cases were divided into four groups based on the cell count per high-power field. Furthermore, these cases were stratified into two classifications: negative (cell counts 0 and 1) and positive (cell counts 2 and 3).PD-1 = programmed cell death protein 1; PD-L1 = PD-1 ligand; TICs = tumor immune cells.
Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) for PD-1 and PD-L1 on tumor-immune cells. The cases were divided into four groups based on the cell count per high-power field. Furthermore, these cases were stratified into two classifications: negative (cell counts 0 and 1) and positive (cell counts 2 and 3).PD-1 = programmed cell death protein 1; PD-L1 = PD-1 ligand; TICs = tumor immune cells.

FIGURE 4.

Kaplan-Meier curves for (A) progression-free survival and (B) overall survival representing the influence of PD-1 and PD-L1 expression on lymphoma cells (LCs). PD-1 expression on LCs was categorized as negative below 10%. PD-L1 expression on LCs was categorized as negative below 30%.PD-1 = programmed cell death protein 1; PD-L1 = PD-1 ligand
Kaplan-Meier curves for (A) progression-free survival and (B) overall survival representing the influence of PD-1 and PD-L1 expression on lymphoma cells (LCs). PD-1 expression on LCs was categorized as negative below 10%. PD-L1 expression on LCs was categorized as negative below 30%.PD-1 = programmed cell death protein 1; PD-L1 = PD-1 ligand

PD-1 and PD-L1 expression in association with clinicopathological characteristics of patients with diffuse large B-cell lymphoma, not otherwise specified

PD-1 expression on TICs PD-1 expression on LCs PD-L1 expression on TICs PD-L1 expression on LCs
[N, (%)] Positive Negative p value Positive Negative p value Positive Negative p value Positive Negative p value
Total 83 (38.4) 133 (61.6) 19 (8.8) 197 (91.2) 135 (62.5) 81 (37.5) 14 (6.5) 202 (93.5)
Age 0.775 0.466 0.885 0.406
  ≤60 31 (14.4) 53 (24.5) 9 (4.2) 75 (34.7) 53 (24.5) 31 (14.4) 7 (3.2) 77 (35.6)
  >60 52 (24.1) 80 (37.0) 10 (4.6) 122 (56.5) 82 (38.0) 50 (23.1) 7 (3.2) 125 (57.9)
Sex 0.889 0.811 0.265 1.000
  Male 39 (18.1) 65 (30.1) 10 (4.6) 94 (43.5) 61 (28.8) 43 (19.9) 7 (3.2) 97 (44.9)
  Female 44 (20.4) 68 (31.5) 9 (4.2) 103 (47.7) 74 (34.2) 38 (17.6) 7 (3.2) 1,5 (48.6)
Ann Arbor stage 1.000 1.000 0.116 0.134
  I–II 32 (14.8) 52 (24.1) 7 (3.2) 77 (35.6) 47 (21.8) 37 (17.1) 3 (1.4) 81 (37.5)
  III–IV 51 (23.6) 81 (37.5) 12 (5.6) 120 (55.6) 88 (40.7) 44 (20.4) 11 (5.1) 121 (56.0)
Involvement of an extranodal organ 0.643 0.412 0.332 0.738
  Yes 33 (18.9) 39 (22.3) 8 (4.6) 64 (36.6) 44 (25.1) 28 (16.0) 3 (1.7) 69 (39.4)
  No 43 (24.6) 60 (34.3) 7 (4.0) 96 (54.9) 71 (40.6) 32 (18.3) 6 (3.4) 97 (55.4)
Involvement of spleen 0.847 1.000 0.540 1.000
  Yes 15 (9.2) 19 (11.7) 3 (1.8) 31 (19.0) 25 (15.3) 9 (5.5) 1 (0.6) 33 (20.2)
  No 61 (37.4) 68 (41.7) 11 (6.7) 118 (72.4) 87 (53.4) 42 (25.8) 7 (4.3) 122 (74.8)
B symptoms 0.366 0.598 0.536 0.085
  Yes 27 (14.1) 49 (25.5) 5 (2.6) 71 (37.0) 52 (27.1) 24 (12.5) 9 (4.7) 67 (34.9)
  No 50 (26.0) 66 (34.4) 11 (5.7) 105 (54.7) 73 (38.0) 43 (22.4) 5 (2.6) 111 (57.8)
IPI score 0.780 0.228 0.575 1.000
  0–2 45 (20.8) 69 (31.9) 13 (6.0) 101 (46.8) 69 (31.9) 45 (20.8) 7 (3.2) 107 (49.5)
  3–5 38 (17.6) 64 (29.6) 6 (2.8) 96 (44.4) 66 (30.6) 36 (16.7) 7 (3.2) 95 (44.0)
Hans Algorithm classification 0.258 0.224 0.887 0.047
Non-GCB 31 (14.4) 61 (28.2) 11 (5.1) 88 (37.5) 58 (26.9) 34 (15.7) 10 (4.6) 82 (38.0)
GCB 52 (24.1) 72 (33.3) 8 (3.7) 116 (53.7) 77 (35.6) 47 (21.8)) 4 (1.9) 120 (55.6)
Patients’ outcome 0.124 0.639 0.779 0.788
Alive 45 (20.8) 57 (26.4) 10 (4.6) 92 (42.6) 65 (30.1) 37 (17.1) 6 (2.8) 96 (44.4)
Dead 38 (17.6) 76 (35.2) 9 (4.2) 105 (48.6) 70 (32.4) 44 (20.4) 8 (3.7) 106 (49.1)

Description of the PAX5, PD-1 And PD-L1 antibodies and immunohistochemistry staining protocols

Primary Ab Clone Vendor Reaction type Antigen retrieval [100°C] Ab dilution Ab incubation time [min] IHC detection kit
PAX5 SP34 Ventana Nuclear CC1 56 min RTU 32 (37°C) UltraView Universal Alkaline Phosphatase Red
PD-1 NAT105 Dako Cytoplasmic, Membranous CC1 88 min 1:200 60 (37°C) OptiView DAB
PD-L1 SP263 Ventana Cytoplasmic, Membranous CC1 64 min RTU 16 (37°C) OptiView DAB

Univariate and multivariate analysis of the patients’ survival based on their clinicopathological characteristics and PD-1 and PD-L1 expressions on lymphoma cells and tumor-infiltrating immune cells in tissue samples of diffuse large B-cell lymphoma, not otherwise specified

Univariate analysis Multivariate analysis
PFS OS PFS OS
p value Median when patients have relapse [months] p value Median when patients died [months] p value HR (95% CI) p value HR (95% CI)
Age ≤ 60 vs. > 60 0.330 91.8 vs. 59.7 < 0.001 110.1 vs. 73.5 < 0.001 2.907 (1.710–4.940)
Sex Male vs. Female 0.945 69.1 vs. 80.9 0.324 78.3 vs. 90.8
Ann Arbor stage I–II vs. III–IV 0.044 91.3 vs. 59.7 < 0.001 113.8 vs. 72.0 0.845 1.072 (0.532–2.130) 0.073 1.654 (0.955–2.865)
Involvement of an extranodal organ (−) vs. (+) 0.886 77.4 vs. 74.1 0.451 81.8 vs. 82.3
Involvement of the spleen (−) vs. (+) 0.915 69.9 vs. 81.8 0.844 80.1 vs. 81.8
B symptoms (−) vs. (+) 0.025 85.3 vs. 30.8 0.004 91.8 vs. 65.3 0.338 1.319 (0.748–2.326) 0.170 1.354 (0.879–2.087)
IPI score 0–2 vs. 3–5 0.006 88.8 vs. 29.3 < 0.001 101.2 vs. 62.7 0.048 1.945 (1.005–3.767) 0.494 1.205 (0.706–2.058)
Hans classification Non-GCB vs. GCB 0.914 66.5 vs. 80.7 0.095 77.6 vs. 85.9
PD-1 on TICs (−) vs. (+) 0.797 81.6 vs. 76.0 0.478 85.9 vs. 80.7
PD-1 on LCs (−) vs. (+) 0.657 77.8 vs. 76.0 0.882 84.9 vs. 76.3
PD-L1 on TICs (−) vs. (+) 0.955 85.9 vs. 76.2 0.623 111.0 vs. 79.2
PD-L1 on LCs (−) vs. (+) 0.015 77.7 vs. 15.6 0.373 85.1 vs. 22.3 0.034 2.393 (1.070–5.352)

Clinicopathological characteristics of the Slovenian patient cohort (N = 216) included in the analysis

PD-1 on TICs Expression PD-1 on LCs Expression PD-L1 on TICs Expression PD-L1 on LCs Expression
(N, %) Positive Negative Positive Negative Positive Negative Positive Negative
All cases (N = 216) 83 133 19 197 135 81 14 202
Non-GCB subtype (N = 92) 31 (37.3) 61 (45.9) 11 (57.9) 81 (41.1) 58 (43.0) 34 (42.0) 10 (71.4) 82 (40.6)
GCB subtype (N = 142) 52 (62.7) 72 (54.1) 8 (42.1) 116 (58.9) 77 (57.0) 47 (58.0) 4 (28.6) 120 (59.4)
Non-GCB versus GCB subtype (p value) 0.258 0.224 0.887 0.047
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