Recently, in the field of cancer treatment, the paradigm has changed to immunotherapy that activates the immune system to induce cancer attacks. Among them, immune checkpoint inhibitors (ICI) are attracting attention as excellent and continuous clinical results. However, it shows not only limitations such as efficacy only in some patients or some indications, but also side-effects and resistance occur. Therefore, it is necessary to understand the factors of the tumor microenvironment (TME) that affect the efficacy of immunotherapy, that is, the mechanism by which cancer grows while evading or suppressing attacks from the immune system within the TME. Tumors can evade attacks from the immune system through various mechanisms such as restricting antigen recognition, inhibiting the immune system, and inducing T cell exhaustion. In addition, tumors inhibit or evade the immune system by accumulating specific metabolites and signal factors within the TME or limiting the nutrients available to immune cells. In order to overcome the limitations of immunotherapy and develop effective cancer treatments and therapeutic strategies, an approach is needed to understand the functions of cancer and immune cells in an integrated manner based on the TME. In this review, we will examine the effects of the TME on cancer cells and immune cells, especially how cancer cells evade the immune system, and examine anti-cancer strategies based on TME.

Significance: Cellular subpopulations in the bone marrow play distinct and unexplored functions in the regulation of the skeleton. A type of blood cell that resides in the bone marrow termed “osteal macrophage” was found to play a role in bone homeostasis by supporting bone formation and mediating parathyroid hormone-dependent bone regeneration. Furthermore, induction of cell death in mature macrophages activated the specialized process of efferocytosis (clearance of dead and dying cells), leading to a marrow microenvironment that supported bone formation.

Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis. We investigated the role of FXR in regulating bone metabolism. We identified the expression of FXR in calvaria and bone marrow cells, which gradually increased during osteoblastic differentiation in vitro. In male mice, deletion of FXR (FXR^−/−) in vivo resulted in a significant reduction in bone mineral density by 4.3% to 6.6% in mice 8 to 20 weeks of age compared with FXR^+/+ mice. Histological analysis of the lumbar spine showed that FXR deficiency reduced the bone formation rate as well as the trabecular bone volume and thickness. Moreover, tartrate-resistant acid phosphatase (TRACP) staining of the femurs revealed that both the osteoclast number and osteoclast surface were significantly increased in FXR^−/− mice compared with FXR^+/+ mice. At the cellular level, induction of alkaline phosphatase (ALP) activities was blunted in primary calvarial cells in FXR^−/− mice compared with FXR^+/+ mice in concert with a significant reduction in type I collagen a1(Col1a1), ALP, and runt-related transcription factor 2 (Runx2) gene expressions. Cultures of bone marrow–derived macrophages from FXR^−/− mice exhibited an increased number of osteoclast formations and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In female FXR^−/− mice, although bone mineral density (BMD) was not significantly different from that in FXR^+/+ mice, bone loss was accelerated after an ovariectomy compared with FXR^+/+ mice. In vitro, activation of FXR by bile acids (chenodeoxycholic acid [CDCA] or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced extracellular signal-regulated kinase (ERK) and β-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol (FOH 1%) diet marginally prevented ovariectomy (OVX)-induced bone loss and enhanced bone mass gain in growing C57BL/6J mice. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of the bone remodeling pathways; ie, bone formation and resorption. © 2013 American Society for Bone and Mineral Research.

Background: Distant metastasis, generally to lung and bone, is rare in differentiated thyroid carcinoma (DTC) and the prognosis is still elusive. We investigated long-term outcomes of lung metastasis in DTC patients and its prognostic factors. Methods: A retrospective review was performed of 4572 patients who underwent surgery for DTC from 1962 to 2009 at Seoul National University Hospital. Among them, 164 patients were identified with lung metastasis and 152 patients were enrolled in the final analysis. Poor prognosis was defined as progressive disease or death. Results: Of these 152 patients, 10- and 20-year survival rates were 85.0% and 71.0%, respectively. No evidence of disease, stable disease, progressive disease, and death was identified in 22.4%, 28.3%, 35.5%, and 13.8%, respectively, after 11 years of median follow-up (range 2–41 years). Older age at diagnosis (≥45 years), primary tumor size ≥2 cm, follicular thyroid cancer, metastasis diagnosed after initial evaluation or ¹³¹ I remnant ablation (late metastasis), multiple metastases other than lung, ¹³¹ I nonavidity, and the presence of macronodules (≥1 cm) were more frequent in poor prognoses. Cox proportional hazard ratio for progression-free survival showed that ¹³¹ I nonavidity was the only independent predictive factor for poor prognosis. Conclusions: The prognosis of lung metastasis from DTC in Korea within this study was favorable. ¹³¹ I nonavidity, observed more frequently in late metastasis, was the only independent factor predicting poor prognosis.

Background: Active surveillance (AS) is an alternative to thyroidectomy for the management of low-risk papillary thyroid microcarcinoma (PTMC). However, prospective AS data collected from diverse populations are needed. Methods: This multicenter prospective cohort study enrolled patients from three referral hospitals in Korea. The participants were self-assigned into two groups, AS or immediate surgery. All patients underwent neck ultrasound every 6–12 months to monitor for disease progression. Progression under AS was evaluated by a criterion of tumor size increment by 3 mm in one dimension (3 mm), 2 mm in two dimensions (2 × 2 mm), new extrathyroidal extension (ETE), or new lymph node metastasis (LNM), and a composite outcome was defined using all four criteria. Results: A total of 1177 eligible patients with PTMC (919 female, 78.1%) with a median age of 48 years (range 19–87) were enrolled; 755 (64.1%) patients chose AS and 422 (35.9%) underwent surgery. Among 755 patients under AS, 706 (female 537, 76.1%) underwent at least two ultrasound examinations and were analyzed. Over a follow-up period of 41.4 months (standard deviation, 16.0), 163 AS patients (23.1%) underwent surgery. Progression defined by the composite outcome was observed in 9.6% (68/706) of patients, and the 2- and 5-year progression estimates were 5.3% and 14.2%, respectively. The observed progression rates were 5.8% (41/706) and 5.4% (38/706) as defined by tumor size enlargement by 3 mm and 2 × 2 mm, respectively, and 1.3% (9/706) and 0.4% (3/706) for new LNM and ETE, respectively. No distant metastases developed during AS. In multivariate logistic regression analysis examining variables associated with progression under AS, age at diagnosis <30 years (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.10 − 7.45), male sex (OR, 2.48; 95% CI, 1.47 − 4.20), and tumor size ≥6 mm (OR, 1.89; 95% CI, 1.09 − 3.27) were independently significant. Conclusions: The progression of low-risk PTMC during AS in the Korean population was low, but slightly higher than previously reported in other populations. Risk factors for disease progression under AS include younger age, male sex, and larger tumor size. Clinical trial registration: Clinicaltrials.gov NCT02938702.