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• W4308378506 abstract "<h3>Background</h3> Lack of response to checkpoint blockade immunotherapy has been linked to a deficiency of immune cell infiltration within the tumor microenvironment (TME). One demonstrated mechanism sufficient for the non-T cell inflamed TME is tumor cell-intrinsic activation of the β-catenin signaling pathway. Using genetically engineered mouse models (GEMMs), tumors constitutively expressing active β-catenin lack a robust endogenous T cell infiltrate and fail to respond to immunotherapies. In support of these mouse studies, human melanoma metastases with increased active β-catenin signaling exhibit decreased numbers of tumor infiltrating Batf3-driven cDC1 and CD3⁺ T cells. However, whether temporal activation and inactivation of b-catenin within the same developing tumor would alter immune cell infiltration is not known. <h3>Methods</h3> A model was created in which tamoxifen-regulated Cre-recombinase mediates BRAF^V600E oncogene activation and PTEN tumor suppressor gene deletion as well as expression of a doxycycline regulatable reverse transactivator. Upon administration of doxycycline via the drinking water to these animals, a non-degradable form of nuclear β-catenin becomes expressed. Immunofluorescence assays were performed assessing the β-catenin expression status in the tumor cells as well as immune cell infiltration within the TME. Additionally, immunotherapy efficacy experiments were performed. <h3>Results</h3> We observed that administration of doxycycline to these animals drove expression of an active form of nuclear β-catenin. Activation of nuclear β-catenin resulted in a 2-fold decrease in the overall CD3⁺ T cells infiltration into the TME. Moreover, this decrease in immune infiltration also resulted in loss of anti-PD-L1 + anti-CTLA-4 therapy efficacy. We next performed studies assessing the kinetics with which β-catenin levels diminish upon doxycycline removal. Switching animals to regular drinking water resulted in complete reduction of nuclear β-catenin levels seven days after doxycycline removal. Interestingly, once nuclear β-catenin levels diminished, we observed re-infiltration of the TME however, these tumors remained unresponsive to anti-PD-L1 + anti-CTLA-4 therapy. <h3>Conclusions</h3> We describe a novel mouse model in which we induce autochthonous melanoma tumors in mice along with inducible expression of a non-degradable, nuclear β-catenin modulated by doxycycline in the drinking water. While removing doxycycline resulted in re-infiltration of CD3+ T cells within the TME, it did not result in restored anti-PD-L1 + anti-CTLA-4 efficacy. Single cell RNAseq and spatial transcriptomics are being performed to determine if an additional immune regulatory event becomes established when b-catenin is on from the birth of the tumor that needs to be overcome. <h3>Acknowledgements</h3> This work was supported by the Wissler Fellowship from the University of Chicago (SS) K99/R00 (NCI; SS), and R35CA210098 (TG)." @default.
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• W4308378506 date "2022-11-01" @default.
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• W4308378506 title "420 Doxycycline regulatable β-catenin demonstrates inducible immune evasion in a melanoma GEM model" @default.
• W4308378506 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0420" @default.
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