Regulatory T Cells and Tumor-Associated Macrophages in the Tumor Microenvironment in Non-Muscle Invasive Bladder Cancer Treated with Intravesical Bacille Calmette-Guérin: A Long-Term Follow-Up Study of a Japanese Cohort

Miyake, Makito; Tatsumi, Yoshihiro; Gotoh, Daisuke; Ohnishi, Sayuri; Owari, Takuya; Iida, Kota; Ohnishi, Kenta; Hori, Shunta; Morizawa, Yosuke; Itami, Yoshitaka; Nakai, Yasushi; Inoue, Takeshi; Anai, Satoshi; Torimoto, Kazumasa; Aoki, Katsuya; Shimada, Kaoru; Konishi, Noboru; Tanaka, Nobumichi; Fujimoto, Kiyohide

doi:10.3390/ijms18102186

Cited by 86 publications

(84 citation statements)

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“…We previously reported that the accumulation of immune-suppressive cells such as regulatory T cells and tumor-associated macrophages in the baseline tumor microenvironment is associated with poor response to intravesical BCG. 31 chemotherapy, other immunotherapy drugs, and radiotherapy. 33,34 The present study is the first to investigate the potential combination of conventional chemotherapy with two different immunotherapies comprising a PD-L1 inhibitor and exogenous GM-CSF in the neoadjuvant setting of radical surgery.…”

Section: Discussionmentioning

confidence: 99%

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

et al. 2019

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Despite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle‐invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony‐stimulating factor (GM‐CSF) to chemoimmunotherapy with programmed cell death protein‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 105 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non‐treated control (vehicle only); (ii) anti‐mPD‐L1 monotherapy; (iii) mGM‐CSF monotherapy; (iv) anti‐mPD‐L1 plus mGM‐CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti‐mPD‐L1; (vii) GC plus mGM‐CSF; and (viii) GC plus anti‐mPD‐L1 plus mGM‐CSF. After completing 2‐week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti‐mPD‐L1 and mGM‐CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti‐mPD‐L1, and mGM‐CSF resulted in longer LR‐free survival and cancer‐specific survival compared to those in other groups. These effects involved an immunotherapy‐related decrease in oncological properties such as tumor invasion capacity and epithelial‐mesenchymal transition. mGM‐CSF significantly decreased the accumulation of myeloid‐derived suppressor cells in both the blood and tumor microenvironment and blood interleukin‐6 levels. Supplementary GM‐CSF to neoadjuvant GC plus PD‐L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

et al. 2019

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Section: The Gold Standard Immunomodulatory Approach To Treat Nmibc: mentioning

confidence: 99%

“…Several published reports have provided evidence that a predominance of immunosuppressive cell types are associated with BCG immunotherapy failure. In particular, the presence of M2-like tumor associated macrophages (TAMs) has consistently been associated with shorter recurrence-free survival and thus a poor response to BCG (7,(9)(10)(11). In NMIBC these TAMs are induced and maintained by Bone Morphogenetic Protein 4 (BMP4) secreted by the tumor cells (12).…”

Section: The Gold Standard Immunomodulatory Approach To Treat Nmibc: mentioning

confidence: 99%

“…Whilst the TAMs are localized in the stroma-tumor margin of NMIBC, infiltrating the tumor area in high-grade tumors, another immunosuppressive cell type the Tregs localize in the stroma around the cancer lesion regardless of tumor stage and grade (9). High Treg counts were shown to be an independent predictor for recurrence following BCG treatment (7,9). Whilst the above studies focused on immunohistochemical analysis of the NMIBC tissue microenvironment, another study characterized immune cell populations in the urine of patients undergoing BCG instillations for the treatment of NMIBC as a surrogate for the bladder tumor microenvironment (14).…”

Section: The Gold Standard Immunomodulatory Approach To Treat Nmibc: mentioning

confidence: 99%

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Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

2020

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It is now well-recognized that the tumor microenvironment (TME) is not only a key regulator of cancer progression but also plays a crucial role in cancer treatment responses. Recently, several high-profile publications have demonstrated the importance of particular immune parameters and cell types that dictate responsiveness to immunotherapies. With this increased understanding of TME-mediated therapy, approaches that increase therapeutic efficacy by remodeling the TME are actively being pursued. A classic example of this, in practice by urologists for over 40 years, is the manipulation of the bladder microenvironment for the treatment of non-muscle invasive bladder cancer (NMIBC) by instillation of intravesical bacillus Calmette-Guerin (BCG). The success of BCG treatment is thought to be due to its ability to induce a massive influx of Th1-polarized inflammatory cells, production of Th1 inflammatory cytokines and the generation of tumor-targeted Th1-mediated cytotoxic responses. Whilst BCG immunotherapy is currently the best treatment for NMIBC, ∼30% of patients show no response to this treatment. Here we present a review highlighting a variety of promising alternative immunotherapies being developed that remodel the bladder tumor microenvironment. These include (1) the use of oncolytic viruses which selectively replicate within cancer cells whilst also modifying the immunological components of the TME, (2) manipulation of the bladder microbiome to augment the response to BCG or other immunotherapies (3) utilizing Toll-like Receptor agonists as anti-tumor agents due to their potent stimulation of innate and adaptive immunity and (4) the growing recognition that immunotherapeutic strategies that will have the largest impact on patients may require multiple therapeutic approaches combined together. The accumulating knowledge on TME remodeling holds promise for providing an alternative therapy for patients with BCG-unresponsive NMIBC.

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“…Many studies have shown that TAMs are associated with poor prognosis of tumors [11][12]. Particularly, the density of TAMs is closely associated with the poor prognosis of some solid tumors, such as breast cancer, gastric cancer, lung cancer, and bladder cancer [13][14]. Thus, the recruitment of macrophages to the TME is important before the transformation to TAMs.…”

Section: Ivyspringmentioning

confidence: 99%

Macrophage Colony-stimulating Factor Mediates the Recruitment of Macrophages in Triple negative Breast Cancer

Lu¹,

Yang²,

Zhang³

et al. 2019

Int. J. Biol. Sci.

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Triple negative breast cancer (TNBC) is characterized by aggressive malignant tumor, poor prognosis and lack of targeted treatment. Several studies have established that macrophages are closely associated with the progression of TNBC. Through immunohistochemical analysis, we found that the infiltration of macrophage in TNBC tissue was more than that in non-triple negative breast cancer (nTNBC) tissue. Furthermore, the conditioned medium (CM) of MDA-MB-231 and HCC1937, the TNBC cell lines, had significant migration-promoted effect on macrophages. However, the macrophages migration-promoted ability of nTNBC cell line MCF-7 was weaker than that of MDA-MB-231 and HCC1937 cells. Mechanistically, MDA-MB-231 and HCC1937 cells secreted more macrophage colony-stimulating factor (M-CSF) than MCF-7, which is the main inducer of macrophage migration, and the secreted M-CSF promoted the increase in actin and the elongation of pseudopodia. When M-CSF was neutralized by antibody, the elongation of macrophage pseudopodia was disappeared and the migration was inhibited. In vivo, there were more macrophages in tumors induced by MDA-MB-231 than MCF-7 did. Therefore, M-CSF specially secreted by TNBC was the important cause of macrophages aggregation in TNBC, which further promoted the aggressiveness of TNBC.

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Regulatory T Cells and Tumor-Associated Macrophages in the Tumor Microenvironment in Non-Muscle Invasive Bladder Cancer Treated with Intravesical Bacille Calmette-Guérin: A Long-Term Follow-Up Study of a Japanese Cohort

Cited by 86 publications

References 34 publications

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

Macrophage Colony-stimulating Factor Mediates the Recruitment of Macrophages in Triple negative Breast Cancer

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