2021 Joint Usage and Research Report
Title of Research Project
Institution
ApplicantJob title

Targeting PARP7 to Improve Cancer Immunotherapy

University of Oslo

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Under35

put a ○

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Professor Jason Matthews

and Name
Institution
Research

Job titlecollaborators

and Name(Please add lines as

Institutionappropriate)

Job title
and Name

Host researcher at IGM

Professor Akinori Takaoka

Purpose of the Research ProjectCancers, such as breast and pancreatic cancer, are devastating(approx. 250 words)

diseases with a very poor prognosis. The composition and immune
status of the tumour microenvironment (TME) is central for diseaseprogression. Cancer immunotherapy is a rapidly growing field andrepresents a paradigm shift in cancer treatment offering a new
therapeutic approach to surgery, conventional chemotherapy, andradiation therapy. One of the most studied targets is the inhibitionof programmed death ligand 1 (PDL1) and its receptor PD1, which
when engaged prevents the overstimulation of the immune system
by deactivating T cells. Type I interferons are central regulators oftumour immune cell infiltration and activation. Together with theTakaoka lab, we recently reported that Poly-ADP-ribose polymerase
7 (PARP7/TIPARP), a negative regulator of type I signalling. The
actions of PARP7 on tumour cells allow them to “hide” from theimmune system by inhibiting IFN production. Thus, restoring
interferon signalling, would in essence release the “brake” thatcancer uses to evade the immune system.
The purpose of this application is to determine if the loss orinhibition of PARP7 alone or in combination with immune
checkpoint inhibition boosts the anti-tumour effects in vitro cell line
and in vivo cancer models.
We have three research objectives: (1) Determine how genetic andpharmacologic targeting of PARP7 signaling influences breast cancer
and pancreatic cancer growth; (2) Investigate the role of PARP7 in T
cell mediated cancer killing (3) Characterize how PARP7 signalinginfluences PC growth in syngeneic mouse studies. Our proposal will
determine the role of PARP7 as a potential therapeutic target on its
own or used as combination treatment with cancer immunotherapy.

Development of the Research

Unfortunately, like many other things during the past year, theProject and Resultscoronavirus pandemic has reduced out research output. Because(approx.. 850 words)of the general travel ban in Norway and Japan, physical*Enter the number of web

meetings from April 1st 2021 until March 31st 2022 were notmeetings.

possible. We did, however, exchange research productivity
updates via email. A formal web-based meeting was notorganized but will be done in the future until other alternatives
are possible.
Over the past year, my lab has established the IFN type signaling
analysis protocol with the help of Prof Takaoka’s lab and theirwillingness to shar their expertise and protocols with us. We haveused the platform to characterize a number of geneticallymodified pancreatic cancer cell lines in which we have knockout
PARP7 expression using CRISPR-Cas. We have created PARP7knockouts in human AsPC1 and SU8686 cells and in mouse
K8484 and CR704 cells. The Two mouse cell lines were generated
from

spontaneous

pancreatictumours

from

LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouseline. As expected PARP7 knockout enhances Type I IFN
signaling. We are characterizing their growth conditions andviability. We are now using various approaches (RNA-seq) toidentify specific gene signatures that are changed by the loss ofPARP7. These experiments are proposed under research objective
1 of our research plan. We have also generated and fully
characterized and highly specific anti-PARP7 antibody that willbe crucial to fully characterize PARP7’s role in pancreatic cancer.
The antibody works best at detecting mouse PARP7, but plans
are underway to develop one that detects human PARP7 as well.
The antibody is a mouse monoclonal which give us an unlimited
supply by purifying it from the hybridomas.
We have tested selective and specific PARP7 inhibitors in the invitro models. We have purchased a commercially available
PARP7 inhibitor that was identified by Ribon Therapeutics(https://ribontx.com),

known

as,

RBN-2397.

RNB-2397iscurrently in a Phase 1 clinical trial designed to assess its

anti-tumor activity in patients with advanced-stage solid tumors(NCT04053673). Their data were published in Cancer Cell in2021(GozgitetalCancer

Cell2021).

Theyreporteddose-dependent reduction of non-small-cell lung carcinoma(NCI-H1373) tumor growth at 30 mg/kg in a xenograft model.
RBN-2397-mediated PARP7 inhibition prevented CT26 colon
tumor growth in a syngeneic mouse model, which was dependenton type I IFN signaling. As expected, in our hands thepharmacological inhibition phenocopies what we observe in thePARP7 knockout cells. We have just recently started thepreliminary studies on the co-culture experiments to investigate
the role of the PARP7 in T cell mediated. Those studies are
ongoing and will be one of our focus this year. Finally, we havebegun our own syngeneic cancer cell experiments using ourParp7 mutant mice and the various genetically modified Parp7
knockout mouse breast cancer and pancreatic cancer lines.
In

preliminarystudies,injectionof Parp7WT E0771

cells

into Parp7H532A mice reduced, but did not prevent, tumor growthcompared with Parp7WT E0771 cells injected into Parp7+/+ mice.
However, Parp7ko E0771 cells injected into Parp7H532A mice failed
to grow into tumors. Our results so far demonstrate that loss ofPARP7 in tumor cells combined with loss in the host are required
to prevent mammary tumor growth. These findings further
support targeting PARP7 for clinical anti-cancer therapy.
【Conference, symposium, workshop etc.】

Publication*EntertheinformationofThe work is in progress and was not presented at a meeting or

conference or journal (vol. page.

conference in 2021 and the first 3 months of 2022. The data were,Year.) where the above work

however, presented during departmental meetings at thewas presented.

University of Oslo. In addition, this ongoing collaboration wasinstrumental in securing new external funding from theNorwegian Research Council to J Matthews in 2021.
【Journals】
No publications this past year.