# Epigenetic Modulation of Immune Tolerance by Ionizing Radiation and Chemotherapy

> **NIH NIH K08** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $164,160

## Abstract

7. PROJECT SUMMARY/ABSTRACT
Sungjune Kim, MD, PhD, PI – PA-14-046 (K08 Resubmission) 11/12/15
Title: Epigenetic modulation of immune tolerance by ionizing radiation and chemotherapy
 Cancer immunotherapy represents a paradigm shift in the management of cancer. Recent successes with
antibody directed therapies for immune modulators CTLA4 and PD1/PDL-1 have altered the landscape of
systemic therapy for melanoma and other solid cancers. While felt to be the most immunogenic among cancers,
melanoma exhibits a wide spectrum of immune tolerance mechanisms, and a majority of patients fail to elicit
clinically significant antitumor immune responses. The response rates for other solid cancers are even lower.
Therefore, developing modalities to enhance immunotherapy, such as radiation therapy (XRT) or conventional
chemotherapy, represent an active area of investigation. Because most cancer patients receive XRT or
chemotherapy at some point in their disease process, harnessing the immunogenic potential of these modalities
is of pivotal importance.
 Our preliminary clinical and preclinical data suggest cytotoxic therapy induce a net positive impact on
immune activation, but limited by tolerogenic mechanisms also evoked. Interestingly, cytotoxic therapy induces a
profound up-regulation of HDAC6, a positive regulator of tolerogenic cytokine IL-10 mediating immune tolerance.
HDAC6 inhibition resulted in radiosensitization and enhanced immunogenicity by cytotoxic therapy. Based on
these observations, we propose to overcome the tolerogenic effects of HDAC6 induction by cytotoxic therapy.
The central hypotheses to be tested in this grant are whether manipulation of HDAC6 augments therapeutic
efficacy and immunogenicity of cytotoxic therapy in melanoma. This research will translate into clinical trials
testing HDAC6-specific inhibitors as a novel class of therapeutic agents to sensitize melanoma for cytotoxic
therapy alone, or in combination with immunotherapy. The proof in concept defined in melanoma will be
applicable to other cancers.

## Key facts

- **NIH application ID:** 9959348
- **Project number:** 5K08CA194273-05
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Sungjune Kim
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $164,160
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959348

## Citation

> US National Institutes of Health, RePORTER application 9959348, Epigenetic Modulation of Immune Tolerance by Ionizing Radiation and Chemotherapy (5K08CA194273-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959348. Licensed CC0.

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