Distinct mechanisms of innate and adaptive immune regulation underlie poor oncologic outcomes associated with KRAS-TP53co-alteration in pancreatic cancer

Autor: Datta, Jashodeep, Bianchi, Anna, De Castro Silva, Iago, Deshpande, Nilesh U., Cao, Long Long, Mehra, Siddharth, Singh, Samara, Rafie, Christine, Sun, Xiaodian, Chen, Xi, Dai, Xizi, Colaprico, Antonio, Sharma, Prateek, Dosch, Austin R., Pillai, Asha, Hosein, Peter J., Nagathihalli, Nagaraj S., Komanduri, Krishna V., Wilson, Julie M., Ban, Yuguang, Merchant, Nipun B.
Zdroj: Oncogene; 20220101, Issue: Preprints p1-15, 15p
Abstrakt: Co-occurrent KRASand TP53mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53co-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-TP53mutated KRAS-altered tumors, KRAS-TP53co-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-TP53co-altered transcriptomes, TP63-defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS-TP53co-altered and KRAS-altered/TP53WTtumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNFsignaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS-TP53co-altered PDAC. Immune subtyping of KRAS-TP53co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS-TP53co-altered “immunoregulatory program” predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.
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