# Correlates of antitumor immunity in colorectal cancers and anti PD1 therapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $374,578

## Abstract

Summary
We recently established that microsatellite instable (MSI) colorectal cancer (CRC), which have a DNA
mismatch repair deficiency and consequently accumulate high density of somatic mutations, exhibits a
robust IFNγhiPD-1hi CD8+ T cell infiltration associated with myeloid expression of the PD-1 ligand, PD-
L1. Further identification of additional T cell checkpoints, including CTLA-4 and LAG-3, suggest that
MSI CRC triggers an endogenous anti-tumor immune response that is counter-regulated by the
coordinate expression of a variety of immunoregulatory ligands. In support of this hypothesis, a clinical
trial initiated at Johns Hopkins Hospital (JHH) found that MSI metastatic CRC (mCRC) patients
demonstrated a 62% objective response rate (ORR) to anti-PD-1 immunotherapy. Importantly,
whereas we identified a subset (14%) of primary microsatellite stable (MSS) CRC which exhibits also
a robust Th1/Tc1-type inflammation, a similar fraction of MSS mCRC was sensitive to anti-PD-1
therapy (11% progression-free disease) suggesting that the efficiency of anti- PD-1 may be associated
with the presence of an endogenous immune response in MSI but also a fraction of immunogenic
MSS CRC. These discoveries raise a number of questions that bear on advances in immunotherapy:
What are the immunologic determinants in the tumor microenvironment that distinguish a responder
from non responder CRC patients to anti-PD-1? Do the somatic mutations of MSS CRC generate
neoantigens (mutation-associated neoantigens or MANAs) that are recognized by the infiltrating T
cells? Does the density over the nature of the mutations drive the intensity of the endogenous immune
response? And finally since MSI CRC represents only 5% of the metastatic CRC, can we identify a
larger population of CRC patient exhibiting an endogenous anti-tumor immune response that will
benefit from checkpoint blockade therapeutic approach? To answer these questions, we propose three
Aims in this proposal: 1) Identifying outlier MSS CRC that exhibit a MSI-like immune signature; 2)
Testing that MSS and MSI CRC-infiltrating CD8+ T cells recognize neoantigens; and 3) Validate
that MANA-specific T cells are unleashed in mCRC responding to anti-PD-1. In finally, this
proposal will define the correlates of the immune response to neoantigens in CRC and will test the
hypothesis that such biomarkers delineate MSS metastatic CRC patients who could benefit from anti-
PD1 therapy.

## Key facts

- **NIH application ID:** 9970429
- **Project number:** 5R01CA203891-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Franck Housseau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,578
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970429

## Citation

> US National Institutes of Health, RePORTER application 9970429, Correlates of antitumor immunity in colorectal cancers and anti PD1 therapy (5R01CA203891-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970429. Licensed CC0.

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