ABSTRACT
Siglec-15, a member of sialic-acid binding immunoglobulin type lectins, is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. While PD-L1 blockade is an important strategy for immunotherapy, its effectiveness is limited. The expression of Siglec-15 has been demonstrated to be predominantly mutually exclusive to PD-L1 in certain cancer histologies. Thus, there is significant opportunity for Siglec-15 as an immunotherapeutic target for patients that do not respond to PD-1/PD-L1 inhibition. The aim of this study was to prospectively develop an immunohistochemical (IHC) assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, we create and validate an IHC assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. To find an enriched target, this antibody was first used in a quantitative fluorescence (QIF) assay to screen a broad range of tumor histologies to determine tumor types where Siglec-15 demonstrated high expression. Based on this and previous data, we focused on development of a chromogenic IHC assay for lung cancer. Then we developed a scoring system for this assay that has high concordance amongst pathologist readers. We then use this chromogenic IHC assay to test the expression of Siglec-15 in two cohorts of NSCLC. We found that this assay shows a higher level of staining in both tumor and immune cells compared to previous QIF assays utilizing a polyclonal antibody. However, similar to that study, only a small percentage of positive Siglec-15 cases showed high expression for PD-L1. This validated assay for Siglec-15 expression may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Sialic Acid Binding Immunoglobulin-like Lectins/therapeutic useABSTRACT
PURPOSE: Androgen receptor (AR) is commonly expressed in breast cancers. However, the association between tumor AR status and breast cancer survival is uncertain. Hence, we examined the association between AR status and breast cancer survival in the Nurses' Health Study (NHS). EXPERIMENTAL DESIGN: It was a prospective study of postmenopausal women enrolled in the Nurses' Health Study with stage I to III breast cancer diagnosed between 1976 and 1997 and followed from the date of diagnosis until January 1, 2008 or death. Analyses were conducted using Kaplan-Meier methods and Cox proportional hazard models, to determine the association of AR status with survival outcomes adjusting for covariates. RESULTS: Among 1467 breast cancers, 78.7% were AR-positive (AR+). Among 1,164 estrogen receptor (ER)-positive cases, 88.0% were AR+. AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47-0.99) and overall mortality (HR, 0.70; 95% CI, 0.53-0.91) after adjustment for covariates. In contrast, among women with ER-negative tumors (303 cases), 42.9% were AR+. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94-2.68). CONCLUSIONS: The association of AR status and breast cancer survival is dependent on ER status. In particular, AR expression was associated with a more favorable prognosis among women with ER-positive tumors. Thus, determination of AR status may provide additional information on prognosis for postmenopausal women with breast cancer, and provide novel opportunities for targeted therapy.
