Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor, we characterized the tumor microenvironment of four commonly used models and demonstrate they encompass a range of immunogenicities, from highly immune infiltrated RENCA tumors to poorly infiltrated B16F10 tumors. Tumor cell lines for each model exhibit different intrinsic factors in vitro that likely influence immune infiltration upon subcutaneous implantation. Similarly, solid tumors in vivo for each model are unique, each enriched in distinct features ranging from pathogen response elements to antigen presentation machinery. As RENCA tumors progress in size, all major T cell populations diminish while myeloid-derived suppressor cells become more enriched, possibly driving immune suppression and tumor progression. In CT26 tumors, CD8 T cells paradoxically increase in density yet are restrained as tumor volume increases. Finally, immunotherapy treatment across these different tumor-immune landscapes segregate into responders and non-responders based on features partially dependent on pre-existing immune infiltrates. Overall, these studies provide an important resource to enhance our translation of syngeneic models to human tumors. Future mechanistic studies paired with this resource will help identify responsive patient populations and improve strategies where immunotherapies are predicted to be ineffective.

Various genotoxic agents cause monoubiquitination of NEMO/ IKK;-the regulatory subunit of IKB kinase (IKK) complexin the nucleus. Ubiquitinated NEMO exits from the nucleus and forms a complex with the IKK catalytic subunits IKKA and IKKB, resulting in IKK activation and, ultimately, nuclear factor-KB (NF-KB) activation. Thus, NEMO ubiquitination is a prerequisite for IKK-dependent activation of NF-KB. However, the IKK activation mechanism is unknown and the NEMOubiquitinating E3 enzyme has not been identified. We found that inhibitors of apoptosis protein (IAP) regulate genotoxic stress-induced NF-KB activation at different levels. XIAP mediates activation of the upstream IKK kinase, TAK1, and couples activated TAK1 to the IKK complex. This XIAPdependent event occurs in response to camptotechin or etoposide/VP16; however, XIAP is dispensable for activation of NF-KB by doxorubicin, which engages a MEK-ERK pathway to activate IKK. We also show that cIAP1 mediates NEMO ubiquitination and cIAP2 regulates an event downstream of NEMO ubiquitination. Our study highlights nonredundant cooperative contributions of IAPs to antiapoptotic NF-KB activation by genotoxic signals beyond their classic caspase inhibitory functions. [Cancer Res 2009;69(5):1782-91]

Per-and polyfluoroalkyl substances (PFAS), which are present in many waters, have detrimental impacts on human health and the environment. Reverse osmosis (RO) and nanofiltration (NF) have shown excellent PFAS separation performance in water treatment; however, these membrane systems do not destroy PFAS but produce concentrated residual streams that need to be managed. Complete destruction of PFAS in RO and NF concentrate streams is ideal, but long-term sequestration strategies are also employed. Because no single technology is adequate for all situations, a range of processes are reviewed here that hold promise as components of treatment schemes for PFAS-laden membrane system concentrates. Attention is also given to relevant

Advances in genetic engineering of non-pathogenic Escherichia coli (E. coli) have made this organism an attractive candidate for gene delivery carrier. However, proliferation and transport behaviors of E. coli in three-dimensional (3D) tumor environment are still unclear. To this end, we developed a novel microfluidics-based tumor model that permitted direct in situ visualization of E. coli in a 3D environment with densely packed tumor cells (B16.F10 or EMT6). The E. coli was engineered to co-express two proteins invasin and mCherry (inv+) so that they had the ability to enter mammalian cells and could be visualized via fluorescence microscopy. E. coli expressing mCherry alone (inv−) was used as the control counterpart. The inv− bacteria proliferated to a higher extent than inv+ bacteria in both the 3D tumor model and a 2D monolayer culture model. Meanwhile, the proliferation appeared to be tumor cell type dependent since bacteria did not proliferate as well in the EMT6 model compared to the B16.F10 model. These differences in bacterial proliferation were likely to be caused by inhibitors secreted by tumor cells, as suggested by our data from the bacterial-tumor cell monolayer co-culture experiment. The bacterial proliferation provided a driving force for cell spreading in the 3D interstitial space of tumors. These findings are useful for researchers to develop novel strategies for improvement of oncolysis or bacteria-mediated gene delivery in cancer treatment.