Table 1.
Studies for the clinical relevance of tumor-infiltrating lymphocytes (TILs) in urological malignancies and retroperitoneal sarcoma.
| Types of Tumor | No. of Patients | Treatment | Makers or Assessment | Assay | Clinical Relevance | Reference No. |
|---|---|---|---|---|---|---|
| Urothelial Carcinoma (UC) | ||||||
| NMIBC | 154 | TURBT followed by intravesical BCG | FOXP3, CD204 | IHC | High Tregs and tumor-associated macrophages were associated with a high risk of intravesical recurrence. | [26] |
| NMIBC | 115 | TURBT | CD3, CD4, CD8, CD20, CD56, CD68, granzyme B | IHC | Low CD3+ TILs and CD8+ TILs were associated with a high risk of intravesical recurrence. | [27] |
| NMIBC | 131 | TURBT | CD4 | IHC | High CD4+ TILs were associated with poor OS. | [28] |
| NMIBC | 102 | TURBT | CD8, CD66b | IHC | High tumor-infiltrating neutrophils and NLR were associated with poor OS. High TILs were related to longer OS. | [29] |
| MIBC | 67 | Radical cystectomy | CD3, CD8 | IHC | High CD8+ TILs and CD3+ TILs in the invasion margin were associated with better DFS and OS. | [30] |
| MIBC | 406 | Radical cystectomy | CD3D, CD4, CD8A | mRNA (TCGA dataset) | High CD3D/CD4 ratio was associated with improved survival. The power was stronger in basal-squamous tumors. | [31] |
| MIBC | 145 | Radical cystectomy | CD8, FOXP3, CD20, PD-1, PD-L1 | IHC | High density of CD8, FOXP3, CD20, and PD-1 was associated with a low risk of recurrence. | [32] |
| Bladder cancer and UTUC | 52 and 18 | Surgical resection | Nine extracellular surface markers | FCM | The immunologically activated group showed poorer PFS and CSS compared that in to the CD4+ T-cell-dominant group in bladder cancer. However, there was no significant difference in UTUC. | [33] |
| UTUC | 162 | Radical nephroureterectomy | PD-L1 | IHC | High PD-L1 expression in tumor cells was associated with shorter CSS. High PD-L1 expression on TILs was associated with longer CSS. | [34] |
| UTUC | 423 | Radical nephroureterectomy | PD-1, PD-L1 | IHC | High PD-1 level was associated with poor CSS and OS. In patients with organ-confined disease (pT2≤, N0/xM0), high PD-L1 was associated with a high risk of recurrence and poor OS. | [35] |
| UTUC | 88 | Radical nephroureterectomy | CD4, CD8, CD20, APE1, NTH1, OGG1, XRCC1, polβ, STING, IRF3, PD-L1, PD-L2 | IHC | High CD8+ TILs were associated with poor DFS. | [36] |
| Metastatic UC | 259 | Platinum-based chemotherapy | Recommendations by an International TILs Working Group 2014 | Hematoxylin and eosin staining | High TIL levels were associated with better OS after chemotherapy both in bladder cancer and UTUC. | [37] |
| Renal cell carcinoma (RCC) | ||||||
| ccRCC | 43 | Untreated stage III/IV disease | CD4, CD45RA, CD8, CD11, HLA-DR, CD3, CD16, CD57 | FCM | An increase in CD8+/CD11- and a decrease in CD4+/CD45RA- cells were observed along with the aggravation of tumor stage and grade. | [39] |
| ccRCC | 473 | Previously treated | Th17, CTL, Tregs, Th2 | mRNA (TCGA dataset) | Long-lived patients have high levels of Th17 and CD8+ T cells, while short-lived patients have high levels of Tregs and Th2. | [40] |
| RCC | 891 | Untreated | M1 macrophages, M2 macrophages, memory CD4+ T, γδ T, CD8+ T, Tregs, naïve CD4+ T, NK cell, mast cells, B cells, DC, monocytes, plasma cells, neutrophils, eosinophils | CIBERSORT | CD8+ T cells were associated with prolonged OS. A higher proportion of regulatory T cells was associated with a poorer outcome. M1 macrophages were associated with a favorable outcome, while M2 macrophages indicated a poorer outcome. | [41] |
| Metastatic ccRCC | 167 | Previously treated | CD8, PD-1, TIM-3, LAG-3 | IHC | A high percentage of CD8+/PD-1+/TIM-3-/LAG-3- cells correlated with high levels of T-cell activation and were associated with longer median irPFS and higher irORR. | [42] |
| ccRCC | 199 | Previously treated | PD-1, FOXP3 | IHC | PD1-positive or FOXP3-positive lymphocytes can be used as significant prognostic indicators, and PD1 positivity could be very helpful in the prediction of latent distant metastasis. | [43] |
| Metastatic ccRCC | 58 | interleukin-2-based immunotherapy | FOXP3 | IHC | Intratumoral FOXP3-positive regulatory immune cells significantly increased during interleukin-2–based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis. | [44] |
| ccRCC | 125 | Radical nephrectomy or nephron-sparing surgery | CD4, FOXP3 | IHC | Increased peritumoral Tregs are associated with a poorer prognosis. | [45] |
| ccRCC | 170 | Radical nephrectomy or nephron-sparing surgery | CD4, CD25, FOXP3 | IHC | Increased number of CD4+CD25+Foxp3+ T cells was not associated with RCC death. In contrast, CD4+CD25+Foxp3- T cells, which may represent a unique set of Tregs or activated helper T cells, were significantly associated with the outcome. | [46] |
| RCC | 97 | Previously treated | CD45, CD3, CD4, CD8, CD45RA, ICOS, Tim3, CD25, PD-1, FOXP3 | FCM | Tumor grade significantly correlated with dysfunction of both CD4+ and CD8+ TILs and the efficacy of nivolumab treatment. | [47] |
| Localized ccRCC | 40 | Radical nephrectomy or nephron-sparing surgery | CD3, CD4, CD8, CD45RA, CCR7, CD69, CD38, CD40L, ICOS, GITR, PD-1, TIM-3, CTLA-4, LAG-3, CD127, CD25 | FCM | Infiltration with CD8+PD-1+Tim-3+Lag-3+ exhausted TILs and ICOS+ Tregs identified patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. | [48] |
| Metastatic RCC | 231 | Tyrosine kinase inhibitors | CD8, PD-1, PD-L1 | IHC | Increased numbers of CD8+ T cells are significantly associated with improved survival in patients with mRCC treated with TKIs. PD-1 could be used as a predictive and prognostic factor. | [49] |
| Prostate cancer (PCa) | ||||||
| Localized PCa | 126 | Radical prostatectomy | CD8, FOXP3 | IHC | High CD8+ TILs were significantly associated with good DFS, whereas FOXP3+Treg tumor infiltration was significantly correlated with poor DFS. | [50] |
| Localized PCa | 535 | Radical prostatectomy | CD8 | IHC | A high density of CD8+ TILs is an independent negative prognostic factor for biochemical failure-free survival. | [51] |
| Biochemical recurence after radical prostatectomy | 22 | Salvage radiotherapy | PD-1, FOXP3 | IHC | High PD-1 and FOXP3+ Treg tumor infiltration was significantly associated with short PFS. | [52] |
| Localized PCa | 75 | Radical prostatectomy | CCR4 | IHC | CCR4+ Tregs are highly infiltrated in the prostate tissue with poor prognosis, with a strong potential to progress to CRPC. | [53] |
| Retroperitoneal sarcoma (RSar) | ||||||
| RSar (various types) | 51 | Surgical resection | PD-1, PD-L1, PD-L2, Ki-67 | IHC | The prognostic value of PD-L1, PD-L2, and PD-1 expression was evaluated, and only high expression of PD-1 was a possible predictor of postoperative recurrence. | [54] |
| RSar (WDLPS) | 6 | Surgical resection | CD4, CD8, CD20 | IHC | CD8+ T cells were mostly seen in scattered gout of the tumor. CD4+ T cells were observed in clusters and follicles. CD20+ cells (B cells) were found almost exclusively in cluster and forming immature follicles. | [55] |
| RSar (WDLPS/DDLPS) | 8 | Surgical resection | CD3, CD4,CD8, PD-1, 4-1BB | IHC FCM |
Cytotoxic CD8+ T cells accounted for 20% of CD3+ T cells. Notably, 65% of CD8+ T cells were positive for PD-1. Immune cell aggregates evaluated by IHC were associated with poorer prognosis in both well-differentiated and dedifferentiated retroperitoneal liposarcoma. | [56] |
| RSar (WDLPS/DDLPS/MLPS/PLPS) | 56 | Surgical resection | CD4, CD8, FOXP3, CD20, PD-1, PD-L1 | IHC | Higher FOXP3+ Treg or PD-1/PD-L1+ cells tended to be associated with poor prognosis. Heterogeneous TIL distribution was found in 50% of patients and tended to correlate with favorable disease-free survival. | [57] |
UC, urothelial carcinoma; NMIBC, non-muscle invasive bladder cancer; MIBC, muscle invasive bladder cancer; TURBT, transurethral resection of bladder tumor; IHC, immunohistochemical staining; TIL, tumor-infltrating lymphocyte; FCM, flow cytometry; Treg, regulatory T cell; UTUC, upper urinary tract urothelial cancer; NLR, neutrophil-to-leukocyte ration; CSS, cancer-specific survival; OS, overall survival; DFS, disease-specific survival; PFS, progression-free survival; NA, not available; ccRCC, clear cell type RCC; CRPC, castration resistant prostate cancer; WDLPS, well differentiated liposarcoma; DDLPS, dedifferentiated liposarcoma; MLPS, myxoid/round cell liposarcoma; PLPS, pleomorphic liposarcoma; PD-L1, programmed cell death ligand-1; PD-L2, programmed cell death ligand-2.