SUMMARY The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4–1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.

In this study assessing the IOR of MSRSGC categories, fair agreement and slight agreement were found for the AUS and SUMP categories, respectively. Observers preferentially used the AUS or benign neoplasm category for SUMP cases, perhaps because of unfamiliarity with SUMP as a diagnostic option. The initial adoption of a new reporting system will require a quality assessment to ensure that the system is reliable and useful for clinicians. Cancer Cytopathol 2018;126:390-6. © 2018 American Cancer Society.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8 þ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8 þ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras-and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8 þ T cells. Distinct from its action on CD4 þ T cells, IL35 signaling in gp130 þ CD8 þ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8 þ T cells via suppression of CXCR3, CCR5, and IFNg expression. Inhibition of STAT3 signaling in tumor-educated CD8 þ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8 þ T cells was driven by B cell-but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8 þ T-cell activation independently of effector or regulatory CD4 þ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35 þ B-cell subset in patients with PDA and demonstrated that the presence of IL35 þ cells predicted increased occurrence of phosphorylated (p)Stat3 þ CXCR3 À CD8 þ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/ STAT3 signaling as an important direct link to CD8 þ T-cell exclusion and immunotherapy resistance in PDA.

Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced. An analysis of tumor-infiltrating immune cells revealed a role for IL35 in the expansion of regulatory T cells and the suppression of CD4 effector T cells. We also detected a robust increase in both the infiltration and activation of cytotoxic CD8 T cells, suggesting that targeting IL35 may be an effective strategy to convert PDA from an immunologically "cold" to "hot" tumor. Although PDA is typically resistant to anti-PD-1 immunotherapy, we demonstrated robust synergistic reduction in tumor growth when IL35 deficiency was combined with anti-PD-1 treatment. These findings provide new insight into the function of IL35 in the pathogenesis of pancreatic cancer and underscore the potential significance of IL35 as a therapeutic target for use in combination immunotherapy approaches in this deadly malignancy. .

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.