{"doi":"10.1101/2022.05.01.490244","title":"Distinct Mechanisms of Innate and Adaptive Immune Regulation Underlie Poor Oncologic Outcomes Associated with <i>KRAS-TP53</i> Co-Alteration in Pancreatic Cancer","abstract":"ABSTRACT Co-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS - TP53 co-alteration is associated with worse survival compared with either KRAS -alone or TP53 -alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non- TP53 mutated KRAS -altered tumors, KRAS - TP53 co-alteration engenders disproportionately innate immune-enriched and CD8 + T-cell-excluded immune signatures. Leveraging in silico, in vitro , and in vivo models of human and murine PDAC, we discover a novel intersection between KRAS - TP53 co-altered transcriptomes, TP63 -defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS - TP53 co-altered and KRAS -altered/ TP53 WT tumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNF signaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS - TP53 co-altered PDAC. Immune subtyping of KRAS - TP53 co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS - TP53 co-altered “immunoregulatory program” predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":307094,"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":0.9433,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":315593,"name":"Anna Bianchi","orcid":"0000-0002-5963-103X","position":1,"is_corresponding":false},{"id":661635,"name":"Iago De Castro Silva","orcid":"0000-0002-3898-6173","position":2,"is_corresponding":false},{"id":643008,"name":"Nilesh Deshpande","orcid":"0000-0002-3912-089X","position":3,"is_corresponding":false},{"id":564722,"name":"Long Cao","orcid":"0000-0002-9380-9954","position":4,"is_corresponding":false},{"id":352775,"name":"Siddharth Mehra","orcid":"0000-0003-1639-8087","position":5,"is_corresponding":false},{"id":661634,"name":"Samara P. 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Hosein","orcid":"0000-0001-8537-6397","position":15,"is_corresponding":false},{"id":336304,"name":"Nagaraj S. Nagathihalli","orcid":"0000-0003-2373-3293","position":16,"is_corresponding":false},{"id":11122,"name":"Krishna V. Komanduri","orcid":"0000-0003-3715-5236","position":17,"is_corresponding":false},{"id":934643,"name":"Julie M. Wilson","orcid":"0000-0003-2510-962X","position":18,"is_corresponding":false},{"id":620649,"name":"Yuguang Ban","orcid":"0000-0002-2874-0647","position":19,"is_corresponding":false},{"id":336305,"name":"Nipun B. 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