TY - JOUR
T1 - Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers
AU - McGrail, Daniel J.
AU - Federico, Lorenzo
AU - Li, Yongsheng
AU - Dai, Hui
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Yi, Song
AU - Lin, Shiaw Yih
AU - Sahni, Nidhi
N1 - Funding Information:
The authors are grateful for assistance from Dong Zhang with histology. This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021, the University of Texas System Rising STARs award, the AASLD Foundation Pinnacle Research Award in Liver Disease, and the University Center Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center to N.S., NIH/NCI 1K22CA214765 to S.Y., NIH R01CA218287 to S.-Y.L. and Susan G. Komen PDF17483544 to D.J.M. The RPPA dataset was supported by NCI P30 CA16672 core grant. We were also grateful to the contributions from the TCGA Research Network Analysis Working Group.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration. This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. These findings demonstrate diverse drivers of immune cell infiltration across cancer lineages and may facilitate the clinical adaption of immunotherapies across diverse malignancies.
AB - To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration. This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. These findings demonstrate diverse drivers of immune cell infiltration across cancer lineages and may facilitate the clinical adaption of immunotherapies across diverse malignancies.
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U2 - 10.1038/s41467-018-03730-x
DO - 10.1038/s41467-018-03730-x
M3 - Article
C2 - 29615613
AN - SCOPUS:85044978378
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1317
ER -