2023 Joint Usage and Research Report
Title of Research Project

Targeting AHR and PARP7 to Improve Cancer
Immunotherapy

InstitutionApplicant

Job title

University of Oslo

Under40

Under35

put a ○

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Professor Jason Matthews

and Name
Institution
Research

Job titlecollaboratorsand Name

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Institutionappropriate)

Job title
and Name

Host researcher at IGM

Professor Akinori Takaoka

Purpose of the Research ProjectType I interferons (IFNs) are cytokines and central regulators(approx. 250 words)of immune cell activation, and T cell mediated tumor cell killing.
Enhancing immune responses in tumors by increasing
proinflammatory cytokine levels or by inhibiting immune
suppressive checkpoint signaling has led to unprecedented
clinical outcomes. However, not all patients respond andtherefore there is a need to identify new therapies for improved
cancer immunotherapy. The aryl hydrocarbon receptor (AHR) isa ligand-activated transcription factor that has been historicallystudied due to its ability to mediate the toxic responses ofenvironmental pollutants, but it is now recognized as an
essential gatekeeper integrating metabolic signals to promote
immunosuppression, regulate effector immune cells, suppress
IFN signaling and enhance tumorigenesis. AHR drives prosurvival processes that increase tumor growth, while its
immunosuppressive actions allow tumor cells to hide from
immunosurveillance. Poly-ADP-ribose polymerase 7 (PARP7) isregulated by AHR and functions to dampen stress responses byrepressing interferon (IFN) signaling. Recently, small molecule
inhibition of PARP7 was shown to restore IFN signaling andrelease the brake that cancer cells use to evade the immunesystem. However, PARP7 negatively regulates AHR, and its loss
increases AHR signaling. Thus, when co-expressed with PARP7,
the increased AHR signaling would be expected to counteract
the potential therapeutic benefit of PARP7 inhibition. The

purpose of this research project is to determine the role of theAHR-PARP7 axis in physiology and disease, as well as
determine if this axis represents a new therapeutic target forchronic inflammatory disease cancer.
Development of the ResearchOver the past year, we have exchanged emails and Professor

Project and Results

Matthews travelled to Hokkaido University in February 2024 to(approx.. 850 words)

meet with Professor Akinori Takaoka and his team to discuss*Enter the number of web

the project and future collaborations. This was a very effective

meetings.

meeting in which we decide on a concrete strategy to continue
to develop our ongoing research collaboration.
Project results:
In this project we hypothesized that loss or inhibition of PARP7

will reduce the growth of solid tumors by increasing anti-tumor
immune responses in an AHR-dependent manner, and therefore
AHR inhibition will improve the therapeutic benefit of PARP7
inhibition. This was tested in two research aims.
In aim 1, we sought to determine how PARP7 inhibition/loss affects
tumor cell growth and IFN/AHR signaling.
Progress: We generated and characterized of PARP7 and AHR knockout
cell lines mouse mammary cancer and pancreatic cancer cell lines
Parp7KO, and AhrKO. However, we were unsuccessful at producing
Parp7KO;AhrKO double knockout cell lines. The Parp7KO, and AhrKO
cell lines were confirmed by western blotting, gene expression analyses
and other cell characterizations. Parp7KO, and AhrKO cells showed aslight reduction in proliferation compared with WT cells, but wereotherwise phenotypically similar to WT cells. As expected Parp7KO in
EO771 mammary cancer cells increase type I IFN responses, while
AhrKO in pancreatic cancer cells had a minimal effect on type I IFN
signalling. However, AHR signalling was ablated in those cells as
reflected by loss of CYP1A1 expression levels.
In aim 2, we determined the impact of inhibition/loss of PARP7
on mammary and pancreatic tumor growth in vivo. We foundthat PARP7 loss had no effect on tumor growth inimmunodeficient mice. In contrast, injection of WT cells into
Parp7H532A mice resulted in smaller tumors comparedwith cells injected into WT mice. Parp7H532A mice (Parp7catalytic mutant mice) injected with Parp7KO cells failed todevelop tumors and those that developed regressed. Our data
highlight the importance of PARP7 in the immune cells andfurther support targeting PARP7 for anticancer therapy.
Pancreatic cancer cells (CR705) deficient in PARP7 resulted insmaller tumors when injected into either wildtype mice or
catalytic mutant Parp7H532A/H532A mice, which harbor a point
mutation in the catalytic domain of PARP7, and tumors
deficient in PARP7 displayed increased infiltration of immunecells. Our data suggest that PARP7 plays an important role in
the antitumor immune mechanisms targeting pancreaticcancer, by reducing tumor growth and by increasing theinfiltration of immune cells. These findings support targeting
PARP7 as a therapeutic strategy in pancreatic cancer.
Pancreatic cancer cells (CR705) deficient in AHR resulted insmaller tumors when injected into either wildtype mice. Tumors
deficient in PARP7 displayed increased infiltration of immune
cells, with a noted increase in inflammatory M1 macrophages.
Collectively, these data suggest that PARP7 plays an importantrole in the antitumor immune mechanisms targeting pancreaticcancer, by reducing tumor growth and by increasing theinfiltration of immune cells. These findings support targeting
PARP7 and AHR as therapeutic strategies for cancer andimproved anti-tumor immunity.
A manuscript summarizing PARP7’s role in mammary cancer
was published in 2023 (see below). Two additional manuscripts,
one describing the role of PARP7 and the other describing therole of AHR in pancreatic cancer will be submitted in fall 2024.
【Conference, symposium, workshop etc.】

Publication*Entertheinformationofconference or journal (vol. page.

FEBS 2023 Advanced course Cellular stress and ADPribosylation 6-11 November 2023 Naples

Year.) where the above work
was presented.
【Journals】
1. Rasmussen, M., Alvik, K., Kannen, V., Olafsen, N.E.,
Erlingsson, L.A.M., Grimaldi, G., Takaoka, A., Grant, D.M.,
Matthews, J. Loss of PARP7 Increases Type I Interferon
Signaling in EO771 Breast Cancer Cells and Prevents
MammaryTumor

GrowthbyIncreasing

Immunity. 2023 Cancers 15(14) 3689.

Antitumor