# Dissecting the tumor-intrinsic and -extrinsic roles of TBK1 in tumor immunity

> **NIH NIH R37** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $594,912

## Abstract

Project Summary
Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway has induced dramatic and durable clinical
responses in melanoma and other cancers. Despite the success of ICB, effective treatment strategies to
overcome resistance to cancer immunotherapy are lacking. TANK-binding kinase 1 (TBK1) is a versatile innate
immune protein kinase nominated as a candidate immune evasion gene in a number of pooled genetic screens.
Using genetic and pharmacologic tools across multiple experimental model systems, we have confirmed a role
for TANK-binding kinase 1 (TBK1) as an immune evasion gene. Targeting TBK1 enhances response to ICB by
lowering the cytotoxicity threshold to effector cytokines (TNFa/IFNg) secreted by immune cells. Tumor cells
lacking TBK1 are primed to undergo RIPK1-dependent cell death in response to TNFa/IFNg. Beyond its effect
on cancer cells, targeting TBK1 in immune cells appears to augment this effect as TBK1 inhibition +/- PD-1
blockade not only promoted accumulation of effector/progenitor exhausted CD8 T cells and M1-like
macrophages, but was sufficient to enhance production of inflammatory cytokines (e.g., IFNg, TNFa) from these
cells. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome
resistance to cancer immunotherapy and raise important questions about the function of TBK1 in cancer cells
versus immune cells in tumor immunity. In this proposal, we aim to confirm and extend these initial observations
and resolve the cell type specific roles of TBK1 in tumor immunity.
In Aim 1, we will determine the cancer cell-specific roles and regulation of TBK1 in resistance to cancer
immunotherapy, by defining the downstream substrates of TBK1 in the setting of ICB resistance and defining
upstream the mechanism(s) of TBK1 regulation promoting immune evasion.
In Aim 2, we define the T cell-specific role of TBK1 in anti-tumor immunity by examining the effect of conditional
deletion of TBK1 in CD8+ T cells. We will use CD8+ T cell specific TBK1 conditional knockout mouse models to
define the effect of TBK1 deletion in T cells on the efficacy of ICB and profile of tumor-infiltrating immune cells,
and CD8+ T cell effector function/dysfunction.
In Aim 3, we will dissect the role of TBK1 in regulating intratumoral myeloid cells. Using myeloid-specific TBK1
conditional knockout mouse models, we will define the effect of myeloid-specific TBK1 deletion on the efficacy
of ICB and the landscape of tumor infiltrating immune cells, as well as the effector function of macrophages and
other myeloid cell populations.

## Key facts

- **NIH application ID:** 10880605
- **Project number:** 5R37CA283560-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Russell William Jenkins
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,912
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880605

## Citation

> US National Institutes of Health, RePORTER application 10880605, Dissecting the tumor-intrinsic and -extrinsic roles of TBK1 in tumor immunity (5R37CA283560-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10880605. Licensed CC0.

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