Table 2.

Macrophages and responses to bladder cancer treatments.

Cell Types and Markers.	Bladder Cancer Cohorts	Treatments	Findings	References
CD68+ (TAM)	40 pTa-pT1 23 ≥ pT2	TURBT or RC	Patients with a high TAM count showed higher rates of cystectomy than those with a low TAM count	Hanada et al. [29]
CD68+ (TAM) and MAC387+ CD68+ (MAC387+ TAM)	81 pTa-pT1 11 pT2	TURBT or RC	TURBT tumors have lower TAM counts than RC tumors High TAM counts were associated with poorer survival in TURBT patients MAC387+ CD68+ cells were associated with poorer survival in RC patients	Bostrom et al. [31]
CD68+ (macrophage) and CD204+ CD68+ (CD204+macrophages)	212 pTa-pT1 90 pT2-pT4	TURBT or RC	Total macrophages and CD204+ macrophages in the stroma were associated with poor OS after surgery	Wang et al. [25]
CD68+ (TAM) and HIF-2α+ CD68+ (HIF-2α+ TAM)	22 pT1 20 pT2 23 pT3 4 pT4	RC	No significant association between TAM indexes and the prognosis in patients undergoing RC HIF-2α+ TAMs were associated with a poor prognosis after RC	Koga et al. [54]
CD33+ HLA-DR− (MDSC)	65 pTa-pT1 44 ≥ pT2	RC	The percentage of total MDSC in PBMC before RC was significantly lower in patients who experienced pathological complete response	Fallah et al. [77]
CD68+ (TAM)	3 pTa 9 pT1 18 pTis	BCG	Higher CD68+ cells in tumor after BCG are correlated with better RFS	Kitamura et al. [78]
CD68+ (TAM)	53 NMIBC	BCG	High TAM is associated with poor RFS in high-risk NMIBC after BCG	Ayari et al. [30]
CD68+ (TAM)	41 CIS	BCG	Low TAM count is associated with good RFS after BCG	Takayama et al. [79]
CD68+ (TAM)	12 pTa 15 pT1	BCG	High TAM count is associated with shorter RFS after BCG treatment	Aliji et al. [80]
CD68+ (TAM)	304 NMIBC	BCG	Pre-BCG treatment TAMs are associated with worse RFS in patients with NMIBC	Kardoust et al. [81]
CD204+ (TAM)	68 pTa 73 pT1 13 pTis	BCG	High counts of TAM showed association with short PFS after BCG	Miyake et al. [34]
CD163+ CD68+ (CD163+ macrophages)	40 pTa 59 pT1	BCG	High density of CD163+ macrophage counts in the stroma but not in the tumor was related with BCG failures	Lima et al. [26]
iNOS+ CD68+ (iNOS+ TAM) and CD163+ CD68+ (CD163+ TAM)	40 NMIBC	BCG	High iNOS+ TAM counts were associated with better DFS after BCG instillation High CD163+ TAM counts were associated with poor DFS after BCG instillation	Suriano et al. [82]
CD68+ (TAM) and CD163+ CD68+ (CD163+ TAM)	9 pTa 21 pT1 10 pTis	BCG	The median number of total CD68+ TAMs and CD163+ TAMs were significantly increased in patients with BCG failure compared to BCG responders High numbers of CD68+ TAMs, high numbers of CD163+ TAMs and a high CD163/CD68 ratio were associated with a greater risk of recurrence after BCG	Pichler et al. [83]
Lin−CD14+ CD33+ HLA-DR− (M-MDSC)	4 pTa 20 pT1 3 pTis 1 pT2	BCG	Low T cell/M-MDSC ratio after BCG treatment correlates with poor RFS & PFS	Chevalier et al. [41]
CD68+ (TAM)	49 pT2 69 ≥ pT3	platinum-based chemotherapy	An immunotype containing low T cells, low NK cells, high Treg and high TAM is associated with increase OS and DFS after chemotherapy in pT3-T4 patients	Fu et al. [24]
DC-SIGN+ CD68+ (DC-SIGN+ TAM)	137 pT2	cisplatin-based chemotherapy	High DC-SIGN+ TAM infiltration was strongly associated with unresponsiveness to adjuvant chemotherapy in MIBC	Hu et al. [46]
Galectin-9+ CD68+ (Gal9+ TAM)	141 ≥ vpT2	platinum-based chemotherapy	Survival benefits after postoperative adjuvant chemotherapy among patients with high Gal9+ TAM, whereas patients with low Gal9+ TAM showed no benefit to chemotherapy	Qi et al. [73]
CD68+ (TAM) and CD163+CD68+ (CD163+TAM)	44 pT2 85 pT3 39 pT4	Adjuvant chemotherapy	Chemotherapy was associated with a longer OS and DSS and showed a trend with a longer RFS in pT3 and pT4 patients with low CD68 expression Chemotherapy was associated with a trend toward longer OS compared with no chemotherapy in pT3 and pT4 patients with low CD163 expression	Taubert et al. [84]
CD33+ HLA-DR− (MDSC)	49 < pT2 36 ≥ pT2	Neoadjuvant chemotherapy	Circulating MDSCs were negatively associated with pathologic complete response in patients treated with neoadjuvant therapy	Ornstein et al. [85]
PD-L1+ tumor-infiltrating immune cells	Metastatic urothelial carcinoma (IMvigor210)	Atezolizumab	PD-L1 expression on immune cells was significantly associated with response to Atezolizumab	Mariathasan et al. [86]
PD-L1+ tumor-infiltrating immune cells	Metastatic urothelial bladder cancer (IMvigor211)	Atezolizumab	Tumors expressing PD-L1+ tumor-infiltrating immune cells had particularly high response rates	Powles et al. [87]
PD-L1+ tumor-infiltrating immune cells	Metastatic urothelial carcinoma	Atezolizumab	Higher levels of PD-L1 immunohistochemistry expression on immune cells were associated with a higher response rate to Atezolizumab and longer OS	Rosenberg et al. [88]
PD-L1+ tumor-infiltrating immune cells	Metastatic urothelial bladder cancer (IMvigor211)	Atezolizumab	Overexpression of PD-L1 resulted in a more favorable outcome with both chemotherapy and Atezolizumab	Powles et al. [89]
PD-L1+ tumor-infiltrating immune cells	Advanced urothelial cancer (KEYNOTE-045)	Pembrolizumab	The benefit of Pembrolizumab appeared to be independent of PD-L1 expression on infiltrating immune cells	Bellmunt et al. [90]
PD-L1+ cells	Unresectable locally advanced or metastatic urothelial carcinoma (CheckMate 032)	Nivolumab + Ipilimumab	Responses were observed regardless of PD-L1 expression levels	Sharma et al. [91]
M1-like TAM	Metastatic urothelial carcinoma (IMvigor210)	Atezolizumab	M1 frequency is a robust biomarker for predicting the prognosis and response to immune checkpoint blockades	Zeng et al. [92]
Pro-tumorigenic inflammation signature	Metastatic urothelial carcinoma (IMvigor210)	Atezolizumab	Pro-tumorigenic inflammation in individual tumor microenvironments is associated with PD-1 and PD-L1 resistance	Wang et al. [93]
	Metastatic urothelial carcinoma (CheckMate 275)	Nivolumab

BCG: Bacillus Calmette-Guérin; DFS: disease-free survival; FFPE: formalin-fixed paraffin-embedded; MDSC: myeloid-derived suppressor cell; M-MDSC: monocytic-MDSC; MIBC: muscle-invasive bladder cancer; NK cells: natural killer cells; NMIBC: nonmuscle-invasive bladder cancer; OS: overall survival; PBMC: peripheral blood mononuclear cell; PFS: progression-free survival; RC: radical cystectomy; RFS: recurrence-free survival; TAM: tumor-associated macrophage; T cells: lymphocytes; TCGA: The Cancer Genome Atlas; Treg: regulatory T cells; TURBT: trans-urethral resection of bladder tumor.