# Triggering Innate Immunity in Tumor Cells to Overcome Resistance to Immunotherapy

> **NIH NIH K08** · YALE UNIVERSITY · 2020 · $279,077

## Abstract

PROJECT SUMMARY:
 Immune checkpoint inhibition of the PD-1/PD-L1 pathway has demonstrated dramatic and durable
clinical benefit for patients in many cancer types and is increasingly being incorporated into standard of care
treatment regimens. However, in most tumor types, this strategy is effective only for a minority of patients. As
such, there is an urgent need for novel therapeutic approaches to potentiate immune checkpoint blockade and
increase the proportion of patients who benefit from it. We recently used in vivo CRISPR screening in
transplantable mouse tumor models treated with antibodies targeting PD-1 to identify the RNA editing enzyme,
ADAR1, as a novel target for combination immunotherapy. In a manuscript published in Nature, we showed
that loss of ADAR1 can overcome two of the most common and challenging mechanisms of resistance to
immunotherapy: a lack of infiltration of anti-tumor immune cells in the tumor microenvironment and the loss of
antigen presentation by the class I major histocompatibility complex on tumor cells. However, the mechanisms
by which loss of ADAR1 achieves these therapeutic goals are unclear. In Aim 1 and Aim 2 of this grant, I
propose to define these mechanisms and to elaborate general principles by which resistance to
immunotherapy can be overcome. More broadly, the identification of ADAR1 as a target for improving
responses to immunotherapy suggests that targeting other enzymes that are associated with a similar auto-
inflammatory phenotype in humans could similarly benefit patients treated with immune checkpoint blockade. I
propose to test this hypothesis in Aim 3 of this grant. If successful, these results will provide a mechanistic
paradigm for overcoming resistance to immunotherapy and identify novel drug targets that trigger a similar
mechanism.
 I am currently a Clinical Fellow in Medical Oncology in the Dana-Farber/Partners CancerCare
Hematology and Oncology Fellowship Program. Over 85% of my time is devoted to my ongoing research
under the mentorship of Dr. Matthew Meyerson (DFCI, Broad Institute) and Dr. Arlene Sharpe (Harvard
Medical School). The remainder of my time is devoted to clinical practice and training at the Dana-Farber
Cancer Institute, primarily in thoracic and gynecologic medical oncology. My goal is to successfully transition
from senior fellow to research instructor and ultimately to an independent investigator in a tenure-track
position. I am applying for the K08 Mentored Clinical Scientist Research Career Development Award to provide
the necessary training and funding to achieve this goal. Under the mentorship of Drs. Meyerson and Sharpe,
and the guidance of my advisory committee (Drs. Golub, Freeman, Hur and Barbie), I will access the
necessary resources and training to develop a successful, independent research program over the funding
period of the award.

## Key facts

- **NIH application ID:** 9870497
- **Project number:** 1K08CA245112-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jeffrey J. Ishizuka
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $279,077
- **Award type:** 1
- **Project period:** 2020-03-02 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870497

## Citation

> US National Institutes of Health, RePORTER application 9870497, Triggering Innate Immunity in Tumor Cells to Overcome Resistance to Immunotherapy (1K08CA245112-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870497. Licensed CC0.

---

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