{"doi":"10.1136/jitc-2020-sitc2020.0230","title":"230 Single cell PIK3 gene expression patterns support duvelisib (PI3K-delta, gamma inhibitor) treatment of melanoma and other tumors after checkpoint inhibitor therapy","abstract":"<h3>Background</h3> Duvelisib, an FDA-approved oral phosphoinositide 3-kinase (PI3K)-δ,γ inhibitor, targets tumor cells of B/T cell malignancies, but may modulate non-malignant immune cells in the tumor microenvironment (TME) of many cancers. PI3K–δ and PI3K–γ downmodulate immunosuppressive Tregs and myeloid cells in solid tumors.<sup>1–3</sup> We used single-cell RNA analysis of PIK3CD and PIK3CG to explore resistance mechanisms to checkpoint inhibitors (CPI). <h3>Methods</h3> Single-cell melanoma (SKCM) RNAseq datasets: GSE120575;<sup>4</sup> CD45+ cells from 48 CPI responders and non-responder tumors, and GSE115978;<sup>5</sup> 33 treatment-naïve and CPI-progressing (resistant) tumors. Cancer cells and CD45+ TME subpopulations, specified by gene expression signatures and tSNE plots, had PI3K gene expressions profiled. Differential gene expression (DE) was gated in MAST/Seurat. Fishers test Odds Ratio (OR) was calculated for ‘high’ expression. <h3>Results</h3> PIK3CD expression is higher in SKCM than most cancers (10.8 median RSEM log 2).<sup>7</sup> By single-cell analysis, PIK3CD (&gt; 0.3 log2 TPM) occurs in 68.2% of cancer cells, with PIK3CB, PIK3CA, and PIK3CG expressed in 32.3%, 12.0%, and 7.2% respectively. PIK3CD-high cancer cells (&gt;4 log2 TPM) have a 711-gene DE gene signature mostly related to immune processes. A higher proportion of cancer cells in CPI resistant tumors express PIK3CD, than untreated tumors (OR 2.02, 95% CI 1.65–2.48, p=3.04 × 10–12), as do PIK3CD+PIK3CG-expressing cancer cells (OR 2.14, 95% CI 1.47–3.13, p=4.2 × 10-5). Additionally, in PI3K–δ or PI3K–γ high melanoma cell lines duvelisib inhibited proliferation, p-AKT and c-myc.<sup>7</sup> PIK3CD and PIK3CG are prominently expressed in many SKCM CD45+ TME cells (84.5% and 31.7% CD45+ respectively). PIK3CD (&gt;0.3 log2 TPM) occurs in a high fraction of T (85.7%), CD8+ T (86.3%), CD4+ T (86.9%), B (78.5%), macrophages (88%), and NK (85%). PIK3CG is highest in B, dendritic, cycling lymphocytes and plasma cells. Strikingly, a significantly higher proportion of PIK3CD+ cells occur in resistant tumors compared to untreated for all CD45+ cells, (OR 1.64, 95% CI 1.40–1.94, p=4.79 × 10-10), CD8+ T (OR 2.15, 95% CI 1.61–2.86, p=6.5 × 10-8), and an exhausted C8+ T subpopulation (OR 3.17, 95% CI 1.89–5.37, p=2.95 × 10-6). PIK3CD+PIK3CG-expressing CD45+ cells are significantly increased in CPI-resistant tumors (OR 1.22, 95% CI 1.07–1.39, p=0.002). <h3>Conclusions</h3> These findings support a mechanism where CPI therapies may contribute to modulation of PI3Kδ expression in cancer cells and the immune TME. The PI3K-δ,γ inhibitor duvelisib is being investigated in combination with CPI and evaluated in the context of CPI resistance in clinical trials: pembrolizumab (HNSC, NCT04193293), and nivolumab (Richter’s Syndrome, NCT03892044). <h3>References</h3> Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer <i>Nature</i> 2014; 510(7505):407–411. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA. PI3Kγ is a molecular switch that controls immune suppression. <i>Nature</i> 2016; 539(7629):437–442. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. <i>Nature</i> 2016; 539(7629):443–447. Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzil","journal":"Regular and Young Investigator Award Abstracts","year":2020,"id":131552,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":585606,"name":"David T. 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