• PD-1/PD-L1
• T cell
• hepatocellular carcinoma (HCC)
• immunotherapy
• tumor-associated macrophages (TAMs)

• Biophysics
• Immunology
• cancer systems biology
• mathematical biosciences

• cell separation
• cell sorting
• characterization
• dielectrophoresis
• macrophage

• Cancer progression
• Circulatory system
• Immune system
• Neuroendocrine system
• Surgical stress

• Humans
• Neoplasms/pathology
• Immune System

• M2-like tumor-associated macrophages
• T cell subsets
• colorectal cancer
• immunoglobulin-like transcript 5
• immunosuppression

• Esophageal cancer
• Immunotherapy
• Neoadjuvant
• Perioperative immunosuppression
• Surgery

• advanced gastric cancer
• conventional care
• enhanced recovery after surgery
• laparoscopic distal gastrectomy
• short-term outcomes

• Adenocarcinoma/diagnosis
• Adenocarcinoma/therapy
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Chemotherapy, Adjuvant
• China/epidemiology
• Enhanced Recovery After Surgery/standards
• Female
• Follow-Up Studies
• Gastrectomy/methods
• Humans
• Incidence
• Laparoscopy/methods
• Length of Stay/trends
• Male
• Middle Aged
• Neoplasm Staging
• Postoperative Complications/epidemiology
• Prospective Studies
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/therapy
• Time Factors
• Young Adult

Mismatch repair proficient colorectal cancer (pMMR CRC) lacks effective treatments and has a poor prognosis, which can be attributed to the complexity of tumor microenvironment. The coordinated function of immune cells is vital to anti-tumor immunity. However, the spatial characteristics of immune cells in the pMMR CRC immune microenvironment and their relationship with clinical prognosis are not fully understood. Meanwhile, the immune modulatory effect of neoadjuvant chemotherapy (NCT), which is the first-line treatment of pMMR CRC, needs further investigation. Therefore, this study aims to explore the spatial dynamics of immune cells and its prognostic value in pMMR CRC.

We analyzed the various immune cells in formalin-fixed, paraffin-embedded tumor tissues which were collected from 77 patients with stage II/III of pMMR CRC, including 39 non-NCT treated and 38 NCT treated patients. We used the optimized multiplex immunohistochemistry (mIHC) to identify and quantify the density, type and location of immune cells in pMMR CRC. Multivariate survival analysis was performed to assess the relationship of immune profiles and clinical prognosis of pMMR CRC patients.

The densities of most T cell subsets, B cells and macrophages were higher in the central region of the pMMR CRC than in the invasion margin. Tumor infiltrating lymphocytes (TILs), especially the infiltration of CD4⁺ GzmB⁺ T cells in the central region of the tumor was identified to be positively correlated with the prognosis of the patients. Multivariate analysis confirmed that CD4⁺ GzmB⁺ T cells population was an independent predictor of disease-free survival (DFS) in non-NCT group. Meanwhile, NCT enhanced the infiltration of CD4⁺ GzmB⁺ T cells in the central region of the pMMR CRC, which was also identified as an independent protective factor of overall survival (OS) and DFS in NCT group.

We demonstrated that the level of CD4⁺ GzmB⁺ T cells located in the center of tumor could provide great prognostic value for pMMR CRC patients. And the application of neoadjuvant chemotherapy further improves the infiltration of CD4⁺ GzmB⁺ T cells in the central compartment. Further studies into the application of CD4⁺ GzmB⁺ T cells in tumor immunotherapy are needed.

• mismatch repair-proficient colorectal cancer
• multiplex immunohistochemistry
• neoadjuvant chemotherapy
• tumor immune microenvironment
• tumor infiltrating lymphocytes

• CCL2
• Treg
• immunosuppression
• lung cancer
• prognosis

Macrophages are an essential component of antitumor activity; however, the role of tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM‐CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM‐CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM‐CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan‐, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.

• colorectal neoplasms
• epithelial-mesenchymal transition
• lymphatic metastasis polarization
• neoplasm metastasis
• tumor-associated macrophages

Cancer treatments are increasingly based on therapeutic antibodies to clear tumors. While in vivo mouse models are useful to predict effectiveness of human antibodies it is not completely clear how useful these models are to test antibodies engineered with enhanced effector functions designed for humans. One of the changes considered for many new antibody-based drugs is the removal of fucose (resulting in afucosylated IgG) which enhances IgG-Fc receptor (FcγR) mediated effector functions in humans through FcγRIIIa. Here we show that afucosylated human IgG1 also have enhanced effector functions against peritoneal metastasis of melanoma cells in mice through the evolutionary related mouse FcγRIV. This shows that afucosylated human IgG is functionally recognized across species and shows that mouse tumor models can be used to assess the therapeutic potential of afucosylated IgG1.

Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (FcγR) IIIa/b, resulting in enhanced antibody dependent cell cytotoxicity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We generated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine FcγRIV, the mouse orthologue of human FcγRIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in FcγRIV^-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies.

• Fc-receptors
• afucosylated IgG
• melanoma

• Metastasis
• Oral cancer
• Targeted cancer therapy
• Tumor Microenvironment

Depletion of tumor associated macrophages and inhibition of tumor angiogenesis have been invoked as the principle mechanisms underlying the antitumor activity of liposomal clodronate (LC). However, previous studies have not examined the effects of LC on systemic antitumor immunity. Here, we used mouse tumor models to elucidate the role of T and NK cells in the antitumor activity elicited by the systemic administration of LC. Strikingly, we found that the antitumor activity of LC is completely abolished in immunodeficient Rag1^−/− mice. Moreover, both Cd4^−/− and Cd8^−/− mice as well as mice depleted of NK cells manifested a significant impaired ability to control tumor growth following LC administration. Treatment with LC did not result in an overall increase in T- or NK-cell numbers in tumors or lymphoid organs, nor was tumor infiltration with T or NK cells altered. However, T and NK cells isolated from the spleen of LC-treated mice exhibited significant increased tumor-specific secretion of interferon γ and interleukin 17 and greater cytolytic activity. We concluded that the antitumor effects of LC are largely dependent on the generation of systemic T-cell and NK- cell activity, most likely owing to the depletion of immune suppressive myeloid cell populations in lymphoid tissues. These findings suggest that the systemic administration of LC may constitute an effective means for non-specifically augmenting the antitumor activity of T and NK cells.

• apoptosis detection
• cancers
• nanoparticle
• pisum sativum agglutinin

• Apoptosis
• Ferric Compounds
• Magnetic Resonance Imaging
• Nanoparticles
• Pharmaceutical Preparations

• R01 CA161953 NCI NIH HHS
• R01 EB026890 NIBIB NIH HHS
• S10 OD016240 NIH HHS
• S10 RR029021 NCRR NIH HHS

At present, the enhanced recovery after surgery (ERAS) protocol is widely implemented in the field of gastric surgery. However, the effect of the ERAS protocol on the long-term prognosis of gastric cancer has not been reported.

To compare the effects of ERAS and conventional protocols on short-term outcomes and long-term prognosis after laparoscopic gastrectomy.

We retrospectively analyzed the data of 1026 consecutive patients who underwent laparoscopic gastrectomy between 2012 and 2015. The patients were divided into either an ERAS group or a conventional group. The groups were matched in a 1:1 ratio using propensity scores based on covariates that affect cancer survival. The primary outcomes were the 5-year overall and cancer-specific survival rates. The secondary outcomes were the postoperative short-term outcomes and inflammatory indexes.

The patient demographics and baseline characteristics were similar between the two groups after matching. Compared to the conventional group, the ERAS group had a significantly shorter postoperative hospital day (7.09 d vs 8.67 d, P < 0.001), shorter time to first flatus, liquid intake, and ambulation (2.50 d vs 3.40 d, P < 0.001; 1.02 d vs 3.64 d, P < 0.001; 1.47 d vs 2.99 d, P < 0.001, respectively), and lower medical costs ($7621.75 vs $7814.16, P = 0.009). There was a significantly higher rate of postoperative complications among patients in the conventional group than among those in the ERAS group (18.1 vs 12.3, P = 0.030). Regarding inflammatory indexes, the C-reactive protein and procalcitonin levels on postoperative day 3/4 were significantly different between the two groups (P < 0.001 and P = 0.025, respectively). The ERAS protocol was associated with significantly improved 5-year overall survival and cancer-specific survival rates compared with conventional protocol (P = 0.013 and 0.032, respectively). When stratified by tumour stage, only the survival of patients with stage III disease was significantly different between the two groups (P = 0.044).

Adherence to the ERAS protocol improves both the short-term outcomes and the 5-year overall survival and cancer-specific survival of patients after laparoscopic gastrectomy.

• Enhanced recovery after surgery
• Conventional management
• Laparoscopic gastrectomy
• Short-term outcomes
• Survival

• Enhanced Recovery After Surgery
• Gastrectomy/adverse effects
• Humans
• Laparoscopy/adverse effects
• Length of Stay
• Postoperative Complications/etiology
• Prospective Studies
• Retrospective Studies
• Stomach Neoplasms/surgery
• Treatment Outcome

• A549 Cells
• Anesthetics, Intravenous/pharmacology
• Anesthetics, Intravenous/therapeutic use
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/drug effects
• PTEN Phosphohydrolase/drug effects
• Propofol/pharmacology
• Proto-Oncogene Proteins c-akt/drug effects
• Signal Transduction/drug effects
• Xenograft Model Antitumor Assays

The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis. Tumor‐associated macrophages (TAMs) are able to orchestrate tumor promoting and suppressing mechanisms in CRC. The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype‐specific metabolic pathways to identify potential new targets for CRC treatment.

A literature search was performed using PubMed, Cochrane and Embase to identify studies on TAMs and their metabolism in CRC. The following search terms were used in various combinations: (obesity OR adiposity OR obese) AND (macrophage OR polarization OR macrophage metabolism) AND ((colon cancer*) OR (colon carcinoma) OR (colonic tumor*) OR (colonic neoplasm[MeSH]) OR (rectal cancer*) OR (rectal carcinoma) OR (rectal tumor*) OR (rectal neoplasm[MeSH]) OR (colorectal cancer*) OR (colorectal carcinoma) OR (colorectal tumor*) OR (colorectal neoplasm[MeSH])). Studies including data on the phenotype and metabolism of TAMs in CRC were analyzed.

Evidence for the prognostic utility of macrophage markers in CRC is currently evolving, with a particular role of stage‐dependent cellular metabolism profiles of TAMs. Itaconate is one of the metabolites produced by proinflammatory subtypes of TAMs and it is known to have tumor promoting effects. Metabolic pathways that are involved in macrophage activation and reprogramming play a role in a chronic inflammatory setting, consequently affecting the onset and development of CRC.

Tumor‐promoting metabolites, such as itaconate, are directly regulating these mechanisms, thereby triggering carcinogenesis. Metabolic reprogramming in TAMs can build a bridge between metabolic dysfunction and the onset and progression of CRC through inflammatory pathways, particularly in younger patients with early‐onset CRC.

• adiposity
• colonic neoplasms
• colorectal neoplasms
• obesity
• rectal neoplasms
• tumor‐associated macrophages

• colorectal cancer
• diet
• gut
• inflammation
• intestine
• macrophage
• microbiota
• tumor-associated macrophage

• Clinical outcomes
• ERAS pathway
• Gastric cancer
• Laparoscopic distal gastrectomy
• Randomized controlled trial
• Traditional treatment

• Adenocarcinoma/surgery
• Adolescent
• Adult
• Aged
• Disease-Free Survival
• Enhanced Recovery After Surgery
• Evaluation Studies as Topic
• Female
• Follow-Up Studies
• Gastrectomy/methods
• Humans
• Laparoscopy/methods
• Length of Stay
• Male
• Middle Aged
• Multicenter Studies as Topic
• Postoperative Complications
• Prognosis
• Prospective Studies
• Randomized Controlled Trials as Topic
• Stomach Neoplasms/surgery
• Young Adult

• 81572314 Innovative Research Group Project of the National Natural Science Foundation of China

• Gefitinib
• Metastasis-associated macrophages
• Osteosarcoma
• Surgery-accelerated metastasis

• Animals
• Bone Neoplasms
• Cell Line, Tumor
• Disease Models, Animal
• Gefitinib
• Lung Neoplasms/drug therapy
• Mice
• Neoplasm Metastasis
• Osteosarcoma/drug therapy

• Elmezzi Foundation
• Swim Across America

Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.

• Cell fusion
• Hybrid formation
• Polyploidization
• Macrophage
• Cancer progression
• Oncologic treatment resistance

• Breast cancer
• CD163
• Intrinsic subtypes
• Ki-67
• Macrophage
• Radiotherapy

• Adult
• Aged
• Biomarkers, Tumor/analysis
• Breast Neoplasms/immunology
• Breast Neoplasms/therapy
• Disease-Free Survival
• Female
• Humans
• Macrophages/immunology
• Mastectomy, Segmental
• Middle Aged
• Radiotherapy, Adjuvant
• Treatment Outcome
• Tumor Microenvironment/immunology

• Svenska Läkaresällskapet
• Forskningsrådet i Sydöstra Sverige

• Microbiota
• arterial thrombosis
• cardiovascular disease
• endothelial cell
• germ-free mouse model
• immunothrombosis
• platelets
• toll-like receptor
• trimethylamine N-oxide
• von Willebrand factor

• Asymptomatic
• Primary tumor resection
• Scoring model
• Stage IV colorectal cancer
• Systemic treatment

• DJ-1
• Gene
• Knockout mice
• Legumain
• Secretion
• Western blotting
• p53

• anesthesia
• gastric cancer
• overall survival
• patient-controlled analgesia
• propofol
• sevoflurane

Guo et al. show that liver tumor-initiating cells (TICs) actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages abolishes tumorigenesis in a manner dependent on the immune system.

Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Mechanistically, activation of the Hippo pathway effector Yes-associated protein (YAP) underlies macrophage recruitment by TICs. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TICs in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages.

• Hippo pathway
• YAP
• immunosurveillance
• liver cancer
• macrophage
• tumor-initiating cell

• Animals
• Cell Hypoxia
• Humans
• Inflammation Mediators/metabolism
• Macrophages/immunology
• Macrophages/metabolism
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/therapy
• Tumor Microenvironment

• 13-1031 Worldwide Cancer Research

Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1α and HIF-1β, in which HIF-1β is constitutively expressed. HIF-1 upregulates several hypoxia-responsive proteins, including angiogenesis factors, glycolysis solution enzymes, and cell survival proteins. HIF-1 is also associated with the degree of inflammation in the tumor region, but the exact mechanism remains unclear. This study aims to identify the molecular mechanism of recruiting monocytes/macrophages by HIF-1α in pancreatic ductal adenocarcinoma (PDAC) and the effects of macrophages on pancreatic stellate cells (PSCs). Immunohistochemistry (IHC) was performed for cluster of differentiation 68 (CD68), HIF-1α, and chemical chemokines 2 (CCL2). Western blot, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation assay, and The Cancer Genome Atlas (TCGA) were used to verify the correlation between HIF-1α and CCL2 at protein and nucleic acid levels. Monocytes/macrophages were co-cultured with PSCs to observe their interaction. Samples showed significant correlation between CD68 and HIF-1α (t-test, p < 0.05). HIF-1α recruited monocytes/macrophages by promoting CCL2 secretion. Moreover, macrophages could accelerate the activation of PSCs. HIF-1α might promote inflammation and fibrosis of PDAC through CCL2 secretion, which may provide a novel target to treat PDAC patients.

• CCL2
• HIF-1
• PDAC
• PSCs
• monocytes/macrophages

• Antigens, CD/metabolism
• Antigens, Differentiation, Myelomonocytic/metabolism
• Biomarkers
• Carcinoma, Pancreatic Ductal/immunology
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/mortality
• Carcinoma, Pancreatic Ductal/pathology
• Cell Line, Tumor
• Chemokine CCL2
• Chemotaxis, Leukocyte
• Humans
• Hypoxia-Inducible Factor 1/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Immunohistochemistry
• Macrophages/immunology
• Macrophages/metabolism
• Pancreatic Neoplasms/immunology
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Pancreatic Stellate Cells/immunology
• Pancreatic Stellate Cells/metabolism

• PDX model
• metastasis
• mouse model
• peritoneal

• Annexin A2
• DJ-1
• Legumain
• p53

• G-CSF
• NK cells
• Th1
• colorectal cancer
• macrophages

• Animals
• Antibodies, Neutralizing/immunology
• Antibodies, Neutralizing/pharmacology
• Colonic Neoplasms/genetics
• Colonic Neoplasms/immunology
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/therapy
• Female
• Granulocyte Colony-Stimulating Factor/antagonists & inhibitors
• Granulocyte Colony-Stimulating Factor/pharmacology
• Killer Cells, Natural/immunology
• Macrophages/immunology
• Mice
• Mice, Inbred C57BL
• T-Lymphocytes/immunology

• P30 CA118100 NCI NIH HHS
• UL1 TR001449 NCATS NIH HHS
• KL2 TR000089 NCATS NIH HHS
• NIH P30CA118100 NCI NIH HHS
• T32AI007538-17-21 NIAID NIH HHS
• UL1 TR000041 NCATS NIH HHS
• T32 AI007538 NIAID NIH HHS
• NIH 8UL1TR000041 NCATS NIH HHS

• Colorectal cancer
• Immune therapy
• Macrophage activation
• Macrophages
• Monoclonal antibodies

The skeleton is one of the most common sites of metastatic disease, affecting a large number of patients with advanced cancer. Although an increasing number of therapies are available for treatment of bone metastasis, this remains incurable, highlighting the need for better understanding of the underlying biology. Metastatic tumour spread to distant organs is a multistage process, involving not only cancer cells but also those of the surrounding host microenvironment. Tumour associated macrophages are multifunctional cells that contribute both to tumour development and response to treatment by regulating adaptive immunity, remodelling of stroma, mediating basement membrane breakdown and angiogenesis. Although direct evidence for a specific role of macrophages in bone metastasis is limited, their involvement in metastasis in general is well documented. In this review we provide an overview of role of macrophages in tumour progression, with particular emphasis on their potential role in bone metastasis.

• Bone metastasis
• Breast cancer
• Macrophages
• Tumour-associated macrophages

• antiangiogenic therapy
• glioblastoma
• myeloid cells
• relapse