Eva Galka

Translational strategies exploiting TNF-|[alpha]| that sensitize tumors to radiation therapy

TNFerade is a radioinducible adenoviral vector expressing tumor necrosis factor-α (TNF-α) (Ad.Egr-TNF) currently in a phase III trial for inoperable pancreatic cancer. We studied B16-F1 melanoma tumors in TNF receptor wild-type (C57BL/6) and deficient (TNFR1,2−/− and TNFR1−/−) mice. Ad.Egr-TNF+IR inhibited tumor growth compared with IR in C57BL/6 but not in receptor-deficient mice. Tumors resistant to TNF-α were also sensitive to Ad.Egr-TNF+IR in C57BL/6 mice. Ad.Egr-TNF+IR produced an increase in tumor-associated endothelial cell apoptosis not observed in receptor-deficient animals. Also, B16-F1 tumors in mice with germline deletions of TNFR1,2, TNFR1 or TNF-α, or in mice receiving anti-TNF-α exhibited radiosensitivity. These results show that tumor-associated endothelium is the principal target for Ad.Egr-TNF radiosensitization and implicate TNF-α signaling in tumor radiosensitivity.

Molecular Mechanisms of Cholangiocarcinogenesis: Are Biliary Intraepithelial Neoplasia and Intraductal Papillary Neoplasms of the Bile Duct Precursors to Cholangiocarcinoma?

Cholangiocarcinoma (CC) is a rare, malignant neoplasm that can develop from any site within the intrahepatic or extrahepatic biliary tree. Although the key steps of cholangiocarcinogenesis remain unknown, it has been hypothesized that CC may develop through two key premalignant precursor lesions: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). These lesions probably are analogous to pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm, respectively. This article outlines the molecular basis of cholangiocarcinogenesis through the BilIN and IPNB pathways. It highlights the genetic mutations that alter cellular proliferation, tumor suppression, and impairment of critical mucinous, cell-adhesion, and matrix proteins.

Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1–Resistant Tumors Leading to Tumor Eradication

Tumor-specific CD8+ T cells temporarily control tumor growth, but eventually tumors can escape. Adoptive transfer of tumor-recognizing CD4+ T cells rescued the function of exhausted CD8+ T cells through co-cross-presentation by stroma, which led to complete tumor eradication. Adoptively transferred CD8+ T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T-cell–mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kb needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+ T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the “exhaustion” markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+ T cells restored the numbers of circulating Ag-specific CD8+ T cells and their intratumoral function, resulting in tumor eradication. These CD4+ T cells had no antitumor effects in the absence of CD8+ T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+ T cells might also be effective in cancer patients when PD-1/PD-L1 blockade does not rescue intratumoral CD8+ T-cell function and tumors persist. Cancer Immunol Res; 5(2); 127–36. ©2017 AACR.

Surgical readmissions: results of integrating pre-, peri- and postsurgical care

To explore the feasibility of recruiting surgical oncology patients and implementing a surgical integrated discharge (SID) programme led by advanced practice providers (APP).