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Distinct mechanisms of innate and adaptive immune regulation underlie poor oncologic outcomes associated with KRAS-TP53 co-alteration in pancreatic cancer

Oncogene volume 41, pages 3640–3654 (2022)Cite this article

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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/TP53WT 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.

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Fig. 1: KRAS-TP53 genomic co-alteration is associated with worse survival and immune exclusion in patients with pancreatic cancer.
Fig. 2: The KRAS-TP53 co-altered transcriptome intersects with TP63-defined squamous transdifferentiation and immune exclusion in PDAC.
Fig. 3: KRAS-TP53 co-alteration encodes a transcriptional program that orchestrates myeloid cell migration and infiltration into the PDAC tumor microenvironment.
Fig. 4: Granulocyte-derived inflammasome and TNF activation are putative mediators of immunoregulation in KRAS-TP53 co-altered PDAC.
Fig. 5: Consensus immune subtyping reveals conflation of intratumor heterogeneity with augmented stemness properties in KRAS-TP53 co-altered PDAC.
Fig. 6: Development of an immunoregulatory transcriptional program associated with KRAS-TP53 co-alteration in PDAC.

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Data availability

The authors declare that the data supporting the findings of this study, and information for retrieval of all external sources of data, are available within the manuscript. The detailed mutational information of tumor samples in the UMiami cohort (n = 245) was collated from commercial vendors in the UMiami Patient Atlas, and putative oncogenic mutations are provided in Table S1.

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Acknowledgements

This work was supported by KL2 career development grant from Miami CTSI under NIH Award UL1TR002736, Stanley Glaser Foundation, American College of Surgeons Franklin Martin Career Development Award, and Association for Academic Surgery Joel J. Roslyn Faculty Award (to JD); NIH R01 CA161976 (to NBM); and NCI/NIH Award P30CA240139 (to JD and NBM).

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Jashodeep Datta, Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Long Long Cao, Siddharth Mehra, Samara Singh, Christine Rafie, Xizi Dai, Austin R. Dosch, Nagaraj S. Nagathihalli & Nipun B. Merchant

  2. Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Jashodeep Datta, Asha Pillai, Peter J. Hosein, Nagaraj S. Nagathihalli, Krishna V. Komanduri & Nipun B. Merchant

  3. Biostatistics and Bioinformatics Shared Resource, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    Xiaodian Sun, Xi Chen, Antonio Colaprico & Yuguang Ban

  4. Department of Surgery, University of Nebraska, Omaha, NE, USA

    Prateek Sharma

  5. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA

    Asha Pillai

  6. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA

    Asha Pillai

  7. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    Peter J. Hosein & Krishna V. Komanduri

  8. PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada

    Julie M. Wilson

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  1. Jashodeep Datta
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Contributions

JD designed the study; JD, NBM provided funding; JD, YB, AB, IDCS, NUD, LLC, SM, SS, CR, XS, XD, AC, PS, ARD performed the experiments; JD, AP, PJH, NSN, JMW, JJK, XC, KVK, NBM provided access to clinical/murine samples; JD, YB, AB, CR wrote the manuscript; all authors reviewed/edited the manuscript.

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Correspondence to Jashodeep Datta.

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Datta, J., Bianchi, A., De Castro Silva, I. et al. Distinct mechanisms of innate and adaptive immune regulation underlie poor oncologic outcomes associated with KRAS-TP53 co-alteration in pancreatic cancer. Oncogene 41, 3640–3654 (2022). https://doi.org/10.1038/s41388-022-02368-w

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