Anticancer efficacy of monotherapy with antibodies to SIRPα/SIRPβ1 mediated by induction of antitumorigenic macrophages

The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPβ1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell–killing activity of macrophages, however. Moreover, knockdown of SIRPβ1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPβ1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPβ1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPβ1 is a potential target for cancer immunotherapy.

Two-Step Method for Assessing Similarity of Random Sets

The paper concerns a new statistical method for assessing dissimilarity of two random sets based on one realisation of each of them. The method focuses on shapes of the components of the random sets, namely on the curvature of their boundaries together with the ratios of their perimeters and areas. Theoretical background is introduced and then, the method is described, justified by a simulation study and applied to real data of two different types of tissue - mammary cancer and mastopathy.

A Study on the Relationship Between Tumor Size, Tumor Grade and Lymph Node Involvement in Canine Mammary Cancer: Simulation of Tumor Behavior in Human Breast Cancer

Background: In the last two decades, canine mammary cancer has played an essential role in human breast cancer research. There are various similarities between biological and clinical features of canine breast cancer and female breast cancer in many cases. Clinical studies and evaluation of prognostic factors in canine mammary cancer can increase reliability in generalizing results to human cancers. This study was performed in the direction of comparative oncology. Methods: We collected clinicopathological data of an invasive type of canine mammary carcinoma from clinical records and pathology reports. Age, tumor laterality, tumor size, lymph node status, and tumor grade were recorded, and the relationships between the parameters were evaluated using linear regression analysis. Results: Ninety-seven patients were included in the study, and the mean age was 10.06 ± 2.73 years. The left mammary gland was involved in 51% of cases, and pT2 was the most common tumor size. Lymph nodes were involved in 27% of patients, and 43% of tumors were grade I. Statistical analysis showed no relationship between tumor size and laterality with other clinicopathological features. However, there was a statistically significant relationship between tumor size and tumor grade, and lymph node status. As the tumor size increased, tumor grade and the risk of lymph node involvement raised. Conclusion: Similar results of this study to breast cancer in women show that canine mammary carcinoma is a suitable model in comparative oncology research. Dogs live shorter than humans so that researchers can get the results of treatment and perform survival rate assessments faster in clinical trials. By considering ethical principles, dogs with breast cancer may replace phases I and II of human clinical trials in some cancer types soon.

INHIBITORY ACTIVITY OF SNAIL (Achatina fulica (Lam.) Bowdich) MUCUS ON GROWTH OF MAMMARY CANCER IN RAT INDUCED WITH DMBA (7,12-DIMETHYLBENZ(α)ANTHRACENE)

Back to nature as a medication concept has been accepted widely because it has fewer side effects than modern medicines. Researches on natural products as anticancer agent therapies are in progress. This present research was conducted to determine that the inhibitory activity of snail (Achatina fulica (Lam.) Bowdich) mucus inhibits the growth rate of mammary cancer in SpragueDawley rats. Five groups of female rats, with four individuals each, were induced with 7,12-dimethylbenz(α)anthracene (DMBA) for five weeks. Snail mucus was applied every seven days to the treated rats with three different dosages (15, 20, and 25 mg/kg BW). Observations were done on diameters and growth rate of the mammary cancer lump developed at the end of week 8, 10, 12, 14, and 16. Histopathological examination was carried out at the end of the 16th week. Inhibitory activity results showed a row of average diameter of the cancerous lumps on rats with the following details. The results obtained from the application of snail mucus at dosage of 15, 20, and 25 mg/kg BW were at 0.40, 0.60, and 0.09 cm respectively along with average growth rate of cancerous lumps at 1.50, 0.75, and 0.25. The histopathology results of the snail mucus treatment at dosage of 15, 20, and 25 mg/kg BW showed normal tissue depiction and similarly normal histopathological form indicated by the presence of their sub-clinic components. The results showed that a snail mucus dose of 25 mg/kg BW was able to perform inhibitory activity on growing mammary cancer in rats induced by DMBA.

756 Identifying the role of B7-H4 as a suppressor of tumor infiltrating lymphocytes and a target for immunotherapy in breast cancer

BackgroundImmune checkpoint inhibitors (ICI) have improved patient survival in some cancer types but yielded limited success in breast cancer. Combinations of ICI (αPD-L1/PD-1) and chemotherapy have been FDA-approved for metastatic TNBC patients, and potentially in the early breast cancer setting, but many patients remain non-responsive to ICI. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with resistance to αPD-L1. We confirmed an inverse expression pattern between B7-H4 and PD-L1 in breast tumor cells, which has previously been noted by others. B7-H4 was expressed in immune-excluded tumors, while PD-L1 was expressed in immune-infiltrated tumors. Based on these findings, we hypothesized ectopic B7-H4 expression would induce αPD-L1 resistance through immune cell suppression in vivo.MethodsUsing an immunocompetent and αPD-L1-sensitive EMT6 orthotopic mammary cancer model, we induced ectopic expression of B7-H4 and performed animal survival studies to assess therapy response, and RNA analysis to assess changes to cell signaling among tumor infiltrating immune cells. Finally, we performed transcriptomic correlation analyses from the cancer cell line encyclopedia dataset to identify potential regulators of B7-H4 in breast cancer.ResultsIn the αPD-L1-sensitive EMT6 mammary cancer model, tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. Additionally, tumor infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. We also observed strong correlation with B7-H4 mRNA and epithelial cell markers, in contrast to gene expression markers of mesenchymal cells.ConclusionsOur data support the hypothesis that B7-H4 induces tumor resistance to αPD-L1 ICI through an immunosuppressive function. Additionally, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 expression independent of PD-L1 regulation.

Dual recombinase action in the normal and neoplastic mammary gland epithelium

We developed a transgenic mouse line that expresses the codon-optimized Flp recombinase under the control of the MMTV promoter in luminal epithelial cells of the mammary gland. In this report, we demonstrate the versatile applicability of the new MMTV-Flp strain to manipulate genes in a temporally and spatially controlled manner in the normal mammary gland, in luminal-type mammary tumors that overexpress ERBB2, and in a new KRAS-associated mammary cancer model. Although the MMTV-Flp is expressed in a mosaic pattern in the luminal epithelium, the Flp-mediated activation of a mutant KrasG12D allele resulted in basal-like mammary tumors that progressively acquired mesenchymal features. Besides its applicability as a tool for gene activation and cell lineage tracing to validate the cellular origin of primary and metastatic tumor cells, we employed the MMTV-Flp transgene together with the tamoxifen-inducible Cre recombinase to demonstrate that the combinatorial action of both recombinases can be used to delete or to activate genes in established tumors. In a proof-of-principle experiment, we conditionally deleted the JAK1 tyrosine kinase in KRAS-transformed mammary cancer cells using the dual recombinase approach and found that lack of JAK1 was sufficient to block the constitutive activation of STAT3. The collective results from the various lines of investigation showed that it is, in principle, feasible to manipulate genes in a ligand-controlled manner in neoplastic mammary epithelial cells, even when cancer cells acquire a state of cellular plasticity that may no longer support the expression of the MMTV-Flp transgene.

Canine mammary cancer in overweight or obese female dogs is associated with intratumoral microvessel density and macrophage counts

Obesity is a major health condition owing to its effects on chronic diseases and cancers in humans, but little information is available regarding the role of obesity in canine mammary cancer (CMC). In the present study, we performed immunohistochemistry to investigate the effect of obesity on CMC by analyzing the number of tumor-associated macrophages, intratumoral microvessel density (iMVD), and the expression of prognostic factors including epidermal growth factor receptor (EGFR), cyclooxygenase 2 (COX-2), and Ki67 in CMC specimens. These data were compared in CMC specimens from lean or ideal body weight (Group 1) versus overweight or obese (Group 2) female dogs ( n = 60 for each group). Associations between obesity status and histologic characteristics, such as histologic subtype, grading, and lymphatic invasion, were also investigated. Compared with lean or ideal body weight dogs, TAM (tumor-associated macrophage) counts ( P < .005) and iMVD ( P < .001) were significantly higher in overweight or obese dogs. CMC specimens of dogs in the overweight or obese group also showed higher histologic grade ( P < .001). In addition, although no association was found between obesity status and either COX-2 or EGFR expression, Ki67 expression was greater in CMC specimens of overweight or obese dogs ( P < .005). The results of this study suggest that obesity may influence CMC development and progression, being associated with higher histologic grade, greater infiltration of TAMs, and increased tumor angiogenesis.