Harnessing Drivers of Pancreatic Cancer Plasticity for Therapeutic Intent

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CRISPR screening identifies T cell-intrinsic regulators of CD3-bispecific antibody responses.

CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased in vitro CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation. These analyses revealed that CD8+ T cells are dependent on CD4+ T cell-derived signaling factors in order to achieve sustained killing in vitro. Moreover, the mammalian target of rapamycin (mTOR) pathway and several other candidate genes were identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation, highlighting promising approaches to enhancing the utility of these potent therapeutics

Therapeutic Assessment of Targeting ASNS Combined with l-Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms

Asparagine deprivation by L-Asparaginase (L-ASNase) is an effective therapeutic strategy in Acute Lymphoblastic Leukemia, with resistance occurring due to upregulation of ASNS,the only human enzyme synthetizing Asparagine1. L-Asparaginase efficacy in solid tumors is limited by dose-related toxicities 2. Large-scale loss of function genetic in vitro screens identified ASNSas a cancer dependency in several solid malignancies 3,4. Here we evaluate the therapeutic potential of targeting ASNS in melanoma cells. While we confirm in-vitro dependency on ASNS silencing, this is largely dispensable for in vivo tumor growth, even in face of asparagine deprivation, suggesting the need to further characterize such pathway to devise novel therapeutic strategies. Using ex vivo quantitative proteome and transcriptome profiling, we characterize the compensatory mechanism elicited by ASNS knockout melanoma cells allowing their survival. Additionally, genome-wide CRISPR screens upon manipulation of aminoacids levels identify BCLXL, MAPK and GCN2 as critical nodes mediating the observed resistance mechanism. Importantly, pharmacological inhibition of such hits synergizes with L-Asparaginase-mediated Asparagine deprivation in ASNS deficient cells suggesting novel potential therapeutic combinations in melanoma

Make EU trade with Brazil sustainable

Brazil, home to one of the planet's last great forests, is currently in trade negotiations with its second largest trading partner, the European Union (EU). We urge the EU to seize this critical opportunity to ensure that Brazil protects human rights and the environment