# (PQ1) Adaptive immune and microbial mechanisms regulating Lynch syndrome penetrance

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $451,010

## Abstract

This study focuses on Provocative Question 1: What molecular mechanisms influence penetrance in
individuals who inherit a cancer susceptibility gene?
 Lynch syndrome is a genetic disease predisposing to colorectal (CRC) and other cancers that affects >1
million Americans. Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2
cause MMR deficiency (dMMR) and Lynch syndrome. Lynch syndrome CRCs have greatly elevated missense
and small in/del frameshift mutation rates. Lynch syndrome has incomplete disease penetrance that varies
widely. Here we will mechanistically elucidate two important questions about Lynch syndrome CRC
penetrance. First, immune checkpoint blockade studies have revealed important roles for adaptive immunity
against tumor mutation associated neoantigens (MANAs) in late stage and metastatic Lynch syndrome /dMMR
malignancies. However, in the setting of pre-malignancy and early-stage CRCs, where the MANA burden is
much lower, does adaptive immunity suppress Lynch syndrome penetrance? Second, the microbiota
Fusobacterium nucleatum (F. nucleatum) is consistently associated with increased CRC risk. For Lynch
syndrome CRCs, what are the mechanisms through which F. nucleatum promotes penetrance? In part these
questions remain unanswered because Lynch syndrome mouse models develop few CRCs. To elucidate the
mechanisms influencing Lynch syndrome CRC penetrance, we have developed the first robust mouse Lynch
syndrome CRC model. In Aim 1 we will elucidate the roles of adaptive immunity mechanisms to reduce mouse -
Lynch syndrome CRC penetrance. We will test hypotheses that neoantigen vaccination reduces overall mouse
Lynch syndrome CRC penetrance, and specifically for CRCs that arise from Lgr5+ cancer stem cells. In Aim 2
we will elucidate mechanisms of F. nucleatum to promote Lynch syndrome CRC penetrance. We will test
hypotheses that F. nucleatum promotes IL17A driven Lynch Syndrome Lgr5+ cancer stem cell proliferation,
that F. nucleatum mono-association promotes mouse Lynch syndrome CRC penetrance, and that vaccination
with F. nucleatum antigens reduces colonization and CRC penetrance in Lynch Syndrome mice. Overall these
studies will use state-of-the-art tools to elucidate adaptive immune mechanisms influencing Lynch syndrome
CRC penetrance.

## Key facts

- **NIH application ID:** 9996331
- **Project number:** 5R01CA231283-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Steven M Lipkin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,010
- **Award type:** 5
- **Project period:** 2018-09-04 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996331

## Citation

> US National Institutes of Health, RePORTER application 9996331, (PQ1) Adaptive immune and microbial mechanisms regulating Lynch syndrome penetrance (5R01CA231283-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9996331. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*