Related Experiment Video

Updated: Aug 8, 2025

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
09:32

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells

Published on: February 8, 2018

14.7K

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade

Douglas B Fox1, Richard Y Ebright1, Xin Hong1,2

  • 1Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, 02114, USA.

NPJ Precision Oncology
|March 2, 2023
PubMed

Insights

The KEAP1/NRF2 pathway influences melanoma patient responses to immune checkpoint blockade (ICB). This pathway

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) therapy shows promise for melanoma treatment.
  • However, a significant number of patients do not respond effectively to ICB.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of the KEAP1/NRF2 pathway in modulating sensitivity to ICB in melanoma.
  • To identify potential mechanisms underlying resistance to ICB therapy.

Main Methods:

  • Single-cell RNA sequencing was performed on patient-derived circulating tumor cells (CTCs) from melanoma patients.
  • Functional characterization was conducted using established mouse melanoma models.

Main Results:

  • The KEAP1/NRF2 pathway was identified as a key modulator of ICB sensitivity, independent of tumor formation.
  • Intrinsic variations in the expression of KEAP1, a negative regulator of NRF2, contribute to tumor heterogeneity.
  • This heterogeneity leads to subclonal resistance to ICB.

Conclusions:

  • The KEAP1/NRF2 pathway represents a novel target for overcoming ICB resistance in melanoma.
  • Targeting this pathway could enhance the efficacy of ICB therapy in non-responsive patients.
  • Tumor heterogeneity driven by KEAP1 expression is a significant factor in ICB resistance.

More Related Videos

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

7.0K
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis07:41

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Published on: March 8, 2022

2.5K

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.7K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.1K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.4K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K