# Targeting an unrecognized checkpoint on T cell function in tumors

> **NIH NIH K08** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $245,776

## Abstract

PROJECT
SUMMARY/ABSTRACT
A diverse accumulation of infiltrating immune cells is a prominent feature of nearly all cancers1. By directing the
effector functions of cancer-killing T cells, the immune system has the ability to specifically target and mediate
clearance of large established tumors2–5. However, T cell effector function is typically constrained within
tumors, allowing disease progression. Recent insights into how tumors limit T cell function have translated into
new classes of cancer treatments such as immune checkpoint blockade (αCTLA-4 and PD-1) and the adoptive
transfer of large numbers of autologous tumor specific T cells6,7. While immune based therapies have
transformed the practice of oncology over a short period of time, such treatments only work in a small
percentage of patients, as cancers deploy multiple and non-redundant means to evade the immune system. As
our knowledge of the biologic drivers of tumor induced T cell dysfunction remains limited, the bounds of cancer
immunotherapy remain undefined.
A high abundance of cell death is found in many tumors and is associated with poor prognosis. Cell death
results in the release of intracellular potassium (K+), thereby increasing the extracellular potassium ([K+]e) the
tumor microenvironment. We first recognized that this that high [K+]e suppresses T cell antitumor function and
cytokine production, limiting antitumor immunity (Eil R et al, Nature 2016 & Science 2019). Mechanistically, K+
mediated suppression of T cell signaling required the phosphatase activity of PP2A. Genetically
reprogramming of T cell K+ transport translated into improved functionality in vitro and in vivo. While these
findings point to an unrecognized ionic checkpoint resulting from cancer cell death byproducts, others have
proposed cell death and tissue damage to increase immune activity due to the release of damage associated
molecular patterns (DAMPs) and inflammasome activation in myeloid cells. However, inflammasome signaling
is also suppressed by high [K+]e. Thus,our central hypothesis is thatintracellular K+ is a central regulator of
immunobiology that can be leveraged to augment T cell antitumor function.
Intrahepatic Cholangiocarcinoma (ICC) is the second most common cause of primary liver cancer and is fatal
in nearly all cases unless surgically resected owing to resistance to cytotoxic and targeted therapies19,20. ICC is
characterized by a high degree of genomic intratumoral heterogeneity and necrosis as well as a recently
appreciated responsiveness to T cell-based immunotherapy, providing an ideal context in which to pursue the
research proposed herein. If successful, the research proposed in this submission will, 1) define the degree of
immune suppression enforced by cell death byproducts in the context of human intrahepatic
cholangiocarcinoma; 2) test novel cancer treatments based on augmenting T cell ion transport 3) clarify
previously unrecognized aspects of cellular biology controlled by intr...

## Key facts

- **NIH application ID:** 10436352
- **Project number:** 5K08CA256179-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Robert Langland Eil
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $245,776
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436352

## Citation

> US National Institutes of Health, RePORTER application 10436352, Targeting an unrecognized checkpoint on T cell function in tumors (5K08CA256179-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436352. Licensed CC0.

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