# PD-L1 inhibition promotes type I interferon responses, enhancing chemotherapy-induced cytotoxicity in cancer cells

> **NIH NIH R21** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $53,996

## Abstract

PROJECT SUMMARY
Immune checkpoint blockade (ICB), for example using anti-PD-L1, is a landmark advance for treating advanced
cancers but is nevertheless still effective in all too few patients. Thus, extensive efforts are directed at identifying
combination therapeutic strategies to improve response rates. We have discovered that PD-L1, in addition to its
role in blocking T cell activation, protects cancer cells against specific chemotherapeutic agents, e.g., cisplatin.
Importantly, this mechanism operates independently of T cell recognition of tumor and the cell-extrinsic immune
system. We found that PD-L1 inhibits the ability of cancer cells to respond to type I interferon (IFN-I) and that
cancer cell-intrinsic responses to IFN-I are critical in increasing cisplatin cytotoxicity. We hypothesize that PD-
L1 inhibitors will enhance the ability of IFN-I to sensitize cancer cells to chemotherapy by a cancer-cell intrinsic
mechanism, independently of the immune system. Here, we propose to identify chemotherapeutic agents and
IFN-I as logical drugs to combine with ICB, to increase response rates in an immune-independent manner.
Aim 1. Determine the ability of the anti-PD-L1 ICB to enhance IFN-I responses and cisplatin toxicity in
lung cancer cells. FDA-approved anti-PD-L1s (atezolizumab, avelumab, and durvalumab) are currently in
clinical use to activate anti-cancer immune responses. However, it has not been assessed how efficiently each
FDA-approved anti-PD-L1 blocks the cancer cell-intrinsic immune-independent function of PD-L1. We will
determine which antibody against PD-L1 enhances IFNβ responses and cisplatin cytotoxicity in small cell lung
carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cell lines, using Western analysis and IncuCyte
real-time cell monitoring. Aim 2. Define the spectrum of therapeutic agents whose cytotoxicity is enhanced
by inhibiting PD-L1. Each chemotherapeutic agent will be affected differently by the cancer cell-intrinsic
function of PD-L1, since each induces cell death by different mechanisms. We will determine which
chemotherapeutic agent kills cancer cells more efficiently in combination with PD-L1 inhibition (knock-down of
PD-L1 or treating with selected antibodies against PD-L1) alone, or by using PD-L1 inhibition plus IFN-I in SCLC
cells. Aim 3. Generate pre-clinical in vivo proof of principle for rational combination therapy. After
selecting the most efficient combination in vitro in SCLC and NSCLC cell lines, we will evaluate the efficacy of
the combination treatment in vivo in NSG mice, which lack most of the immune system, to cleanly evaluate the
cancer cell-intrinsic immune-independent PD-L1-mediated effects.
Impact. The studies proposed here are highly innovative as they propose a paradigm-shifting approach in which
PD-L1 inhibitors are used as reagents to enhance the ability of IFN-I to sensitize cancer cells to chemotherapy
in an immune-independent mechanism. This work will lead to improved understa...

## Key facts

- **NIH application ID:** 10318664
- **Project number:** 5R21CA252387-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** HyeonJoo Cheon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $53,996
- **Award type:** 5
- **Project period:** 2020-12-14 → 2022-03-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318664

## Citation

> US National Institutes of Health, RePORTER application 10318664, PD-L1 inhibition promotes type I interferon responses, enhancing chemotherapy-induced cytotoxicity in cancer cells (5R21CA252387-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10318664. Licensed CC0.

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