Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. On the basis of its histopathology and molecular-genomic changes ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC-xenografts that recapitulate the molecular and biological heterogeneity of human ovarian cancer. Thirty-four EOC-xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC-xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers and develop novel treatment modalities.

Although in vivo targeting of tumors using fluorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell–penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fluorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule αvβ3-integrin antagonist IntegriSense, TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies. Cancer Res; 74(23); 1–10. ©2014 AACR.

Although in vivo targeting of tumors using fluorescently-labeled probes has greatly
gained in importance over the last few years, most of the clinically applied reagents
lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe
(TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface
of a broad variety of human and mouse tumors and metastases, but not on normal
tissues. Due to the rapid turn-over rate of membrane-Hsp70, fluorescently-labeled
TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically
induced and xenograft tumors following intravenous administration, thereby enabling
site-specific labeling of primary tumors and metastases. In contrast to the
commercially available non-peptide small molecule alpha v beta3-integrin antagonist
IntegriSense (trademark), TPP exhibits a significantly higher tumor-to-background contrast and
stronger tumor-specific signal intensity in all tested tumor models. Moreover, in
contrast to IntegriSense (trademark), TPP reliably differentiates between tumor cells and cells
of the tumor microenvironment, such as tumor-associated macrophages and
fibroblasts which were found to be membrane-Hsp70 negative. Therefore, TPP
provides a useful tool for multimodal imaging of tumors and metastases that might
help to improve our understanding of tumorigenesis and allow the establishment of
improved diagnostic procedures and more accurate therapeutic monitoring. TPP
might also be a promising platform for tumor-specific drug delivery and other Hsp70-
based targeted therapies.

The tolerogenic cytokine IL9 promotes T regulatory cell function and allergic airway inflammation, but it has not been extensively studied in cancer. In this report, we used IL9-deficient mice to investigate the effects of IL9 in multiple models of breast and colon cancer development. Eliminating endogenous IL9 enabled sensitization of host T cells to tumors, leading to their early rejection without the requirement of vaccines or immunomodulatory therapies. Notably, IL9-deficient mice acquired immunologic memory, which actively protected from residual disease and tumor rechallenge, an effect linked to activation of CD8+ T cells. Depletion of either CD8+ or CD4+ T cells abolished the benefits of IL9 loss to tumor control. Adoptive transfer experiments showed that T cells from tumor-rejecting IL9-deficient mice retained their effector competency in wild-type animals. Moreover, neutralizing IL9 antibody phenocopied the effects of IL9 gene deletion by slowing tumor progression in wild-type animals. Our results show the ability of IL9 to function as an inhibitor of adaptive immunity that prevents the formation of immunologic memory to a growing tumor, highlighting the potential for IL9 neutralization as a unique tool for cancer immunotherapy. Cancer Res; 74(23); 1–11. ©2014 AACR.

The tolerogenic cytokine IL-9 promotes T regulatory cell function and allergic airway inflammation, but it has not been extensively studied in cancer. In this report, we employed IL-9 deficient mice to investigate the effects of IL-9 in multiple models of breast and colon cancer development. Eliminating endogenous IL-9 enabled sensitization of host T cells to tumors, leading to their early rejection without the requirement of vaccines or immunomodulatory therapies. Notably, IL-9-deficient mice acquired immunologic memory, which actively protected from residual disease and tumor rechallenge, an effect linked to activation of CD8+ T cells. Depletion of either CD8+ or CD4+ T cells abolished the benefits of IL-9 loss to tumor control. Adoptive transfer experiments showed that T cells from tumor-rejecting IL-9-deficient mice retained their effector competency in wild-type animals. Moreover, neutralizing IL-9 antibody phenocopied the effects of IL-9 gene deletion by slowing tumor progression in wild-type animals. Our results show the ability of IL-9 to function as an inhibitor of adaptive immunity that prevents the formation of immunologic memory to a growing tumor, highlighting the potential for IL-9 neutralization as a unique tool for cancer immunotherapy.