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. 2019 Aug;7(16):387.
doi: 10.21037/atm.2019.07.43.

Changes in the tumor immune microenvironment in resected recurrent soft tissue sarcomas

Biqiang Zheng  1   2 , Jian Wang  3   2 , Weiluo Cai  1   2 , Iweng Lao  3   2 , Yingqiang Shi  1   2 , Xiaoying Luo  4 , Wangjun Yan  1   2
Affiliations

Changes in the tumor immune microenvironment in resected recurrent soft tissue sarcomas

Biqiang Zheng et al. Ann Transl Med. 2019 Aug.

Abstract

Background: Little is known about how the tumor immune microenvironment (TIME) is modulated in recurrent soft tissue sarcomas (STS).

Methods: We evaluated CD8+ T cells, CD20+ B cells, Foxp3+ regulatory T cells (Tregs), and programmed cell death ligand 1 (PD-L1) in 72 paired pre-recurrent (1st resected) versus post-recurrent (2nd resected) STS by immunohistochemistry. Correlations with time to recurrence and prognosis were determined.

Results: We found that CD8, PD-L1, CD20, and Foxp3-positive cell counts changed in post-recurrent STS. PD-L1-positive tumor cell and lymphocyte counts increased in post-recurrent STS, whereas CD8+ T cell counts decreased. Changes in CD8+ T cell, CD20+ B cell, and PD-L1+ lymphocyte counts were associated with the time interval between surgeries. At admission, fewer CD8+ T cells were detected in patients with relapse than in newly diagnosed patients. Furthermore, post-recurrent STS with fewer CD8+ T cells compared with pre-recurrent STS were more likely to exhibit re-recurrence. The change in CD8+ T cells was positively associated with overall survival. In multivariate analyses, a decrease in CD8+ T cell counts in post-recurrent STS was an independent unfavorable prognostic factor.

Conclusions: The TIME differs between pre-recurrent STS and post-recurrent STS. The variation in CD8+ T cells and PD-L1 positivity may have essential roles during tumor relapse and provides a basis for determining therapeutic strategies.

Keywords: CD8; Soft tissue sarcomas (STS); programmed cell death ligand 1 (PD-L1); recurrence; tumor immune microenvironment (TIME).

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
IHC analysis of CD8, PD-L1, CD20, and Foxp3 expression in paired STS between the 1st and 2nd surgery. (A) Increased CD8, PD-L1, CD20, and Foxp3-positive cells were observed in paired STS; (B) decreased CD8, PD-L1, CD20, and Foxp3-positive cells were observed in paired STS. IHC, immunohistochemical; PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes; STS, soft tissue sarcomas. Scale bars =10 µm.
Figure 2
Figure 2
Changes in the quantities of CD8, PD-L1, CD20, and Foxp3-positive lymphocytes and PD-L1-positive tumor cells. (A) Mean or median positive lymphocytes for CD8 and Foxp3 and positivity for PD-L1 and CD20 in STS between the 1st and 2nd surgery; (B) change in the number of CD8-positive lymphocytes; (C) change in PD-L1 positivity in tumor cells (T); (D) change in PD-L1 positivity in lymphocytes (L); (E) change in CD20 positivity; (F) Change in the number of Foxp3-positive lymphocytes. PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes; STS, soft tissue sarcomas.
Figure 3
Figure 3
Comparison between the increase, no change, and decrease groups for (A) CD8, (B,C) PD-L1, (D) CD20, and (E) Foxp3 with respect to the interval of time between the 1st and 2nd surgery. The distributions of the three groups for (A) CD8, (B) PD-L1(T), (C) PD-L1(L), (D) CD20, and (E) Foxp3 are displayed, and their relationships with the interval of time were analyzed. A fold change in the relative value (2nd surgery/1st surgery) of >2 (increase group) or <0.5 (decrease group) for (A) CD8, (B) PD-L1(T), (C) PD-L1(L), (D) CD20, and (E) Foxp3 was defined as significant, and patients were divided into three groups (increase, no change, and decrease). PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes.
Figure 4
Figure 4
CD8+ T cells were closely associated with tumor relapse. Comparison of CD8-positive lymphocytes (A) and PD-L1 positivity (B,C) in STS between new diagnosed and recurrent patients. Comparison of CD8-positive lymphocytes (D) and PD-L1 positivity (E,F) in STS between the 1st and 2nd surgery according to patients who were re-recurrent or not after the 2nd surgery. PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes; STS, soft tissue sarcomas.
Figure 5
Figure 5
Survival analysis for patients with increases, no change, and decreases in CD8, PD-L1(T), PD-L1(L), CD20, and Foxp3.Survival analysis for patients with increases, no change, and decreases in (A) CD8, (B) PD-L1(T), (C) PD-L1(L), (D) CD20, and (E) Foxp3. PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes.
Figure S1
Figure S1
IHC analysis of CD8, PD-L1, CD20, and Foxp3 expression. Examples of positive CD8 expression (A), CD20 expression (D), and Foxp3 expression (E) on lymphocytes in human spleen tissue. Examples of the positive control (B) and negative control (C) for PD-L1 expression on human lung cancer tissues with an anti-PD-L1 antibody and isotype control, respectively. Scale bars =10 µm. IHC, immunohistochemical; PD-L1, programmed cell death ligand 1.
Figure S2
Figure S2
Distribution of PD-L1 expression in tumor cells (A,C) and lymphocytes (B,D) in STS depending on histopathologic type at the 1st and 2nd surgery. PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes; UPS, undifferentiated pleomorphic sarcoma; MFS, myxofibrosarcoma, FS, fibrosarcoma; LPS, liposarcoma; LMS, leiomyosarcoma; SS, synovial sarcoma; AS, angiosarcoma; MPNST, malignant peripheral nerve sheath tumor; STS, soft tissue sarcomas.
Figure S3
Figure S3
Comparison of CD20 positivity (A) and Foxp3-positive lymphocytes (B) in STS between the newly diagnosed and recurrent patients. STS, soft tissue sarcomas.
Figure S4
Figure S4
Comparison of CD20 positivity (A) and Foxp3-positive lymphocytes (B) in STS between the 1st and 2nd surgery according to re-recurrent status of patients, after the 2nd surgery. STS, soft tissue sarcomas.
Figure S5
Figure S5
Correlation of CD8+ T cells with survival in STS patients at first surgery (pre-recurrence). Patients were divided into two groups according to the number of CD8+ T cells/HPF. STS, soft tissue sarcomas.
Figure S6
Figure S6
Effects of chemotherapy and/or radiotherapy on the quantities of PD-L1, CD8, CD20, and Foxp3-positive cells. The quantities of PD-L1(T), PD-L1(L), CD8, CD20, and Foxp3-positive cells were compared in paired STS between the 1st and 2nd surgery in patients who underwent post-operative treatment (chemotherapy and/or radiotherapy) or no post-operative treatment. PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes; STS, soft tissue sarcomas.
Figure S7
Figure S7
Effects of chemotherapy or radiotherapy on the quantities of CD8, PD-L1, CD20, and Foxp3-positive cells. Quantities of CD8, PD-L1(T), PD-L1(L), CD20, and Foxp3-positive cells were compared in paired STS between the 1st and 2nd surgery in patients who received radiotherapy (n=8), chemotherapy (n=7), or chemotherapy plus radiotherapy (n=2). PD-L1, programmed cell death ligand 1; PD-L1(T), PD-L1 in tumor cells; PD-L1(L), PD-L1 in lymphocytes; STS, soft tissue sarcomas.
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