# Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $455,145

## Abstract

Summary
Among women, breast cancer (BC) is the most common malignancy, and the second leading cause of cancer
death. Patients with basal/triple negative BC (TNBC) have the poorest clinical outcome with no targeted
therapies available when compared to other molecular subtypes. Fas/CD95 is a well characterized death
receptor that in permissive cells mediates induction of apoptosis when stimulated by its cognate ligand, FasL. It
is now well established that Fas also has multiple nonapoptotic, tumor promoting functions. High Fas
expression is a negative prognostic factor for TNBC. We have previously demonstrated in multiple genetically
engineered mouse tumor models with tissue specific deletion of Fas that cancer cells maintain Fas expression
and without Fas tumors do not grow. However, some tumors still formed in these knock-out (KO) mice due to
‘escapers’ from Cre recombination. It remained unclear whether this activity of Fas was cell autonomous or
required cells of the tumor microenvironment. New preliminary data on a mouse model of TNBC now suggest
that tumor cell expressed Fas exerts an immune suppressive activity promoting recruitment of myeloid derived
suppressor cells (MDSCs) resulting in inhibition of tumor infiltration by natural killer (NK) cells. Most recently
we discovered, KPC2, a novel Fas interaction partner that binds to the C-terminal end and in unstimulated
TNBC cells sequesters both the NF-κB subunit p65 and KPC1, a ubiquitin ligase that degrades the p50
precursor p105. We found that when Fas is eliminated p105 gets degraded shifting the balance of NF-κB
subunits from repressive p50/p50 homodimers to transcriptionally active p50/p65 heterodimers. That in turn
unleashes production of a number of proinflammatory cytokines that regulate the recruitment of a number of
immune cells including NK cells. Based on these preliminary data we hypothesize that in TNBC Fas acts as a
novel immune check point for NK cells likely by remodeling the immune landscape, that a novel Fas bound
protein complex around KPC2 is responsible for this immune suppressive activity of Fas and finally, that
disrupting this interaction unleashes an antitumor activity that can be used to target TNBC cells. These
hypotheses will be studied in two specific aims: Specific Aim 1: Characterize immune suppressive activities of
Fas in triple negative breast cancer. Specific Aim 2: To determine how Fas expression suppresses a
proinflammatory program. The goal of this project is to characterize novel activities of Fas in promoting TNBC
growth and metastasis as well as its immune suppressive function on NK cells. The project will increase our
knowledge on the role of a complex and critical receptor/ligand signaling pair in cancer that has long been
misunderstood. Only recently has inhibition of FasL (and not its use) been recognized as a valuable option for
the treatment of cancer in the clinic. In TNBC our work now points at inhibiting the Fas receptor in addition to
its li...

## Key facts

- **NIH application ID:** 10872213
- **Project number:** 5R01CA267815-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marcus E. Peter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $455,145
- **Award type:** 5
- **Project period:** 2022-07-07 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872213

## Citation

> US National Institutes of Health, RePORTER application 10872213, Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer (5R01CA267815-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872213. Licensed CC0.

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