Related Experiment Video

Updated: Oct 1, 2025

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
07:04

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology

Published on: May 2, 2025

587

Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor

Karl L Banta1, Xiaozheng Xu2, Avantika S Chitre1

  • 1Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Immunity
|March 9, 2022
PubMed

Insights

Dual blockade of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIGIT) enhances anti-tumor CD8+ T-cell responses. This combination therapy is crucial for restoring CD226 signaling and optimizing cancer immunity.

Area of Science:

  • Immunology
  • Cancer Biology
  • T-cell Metabolism

Background:

  • Coinhibitory receptors PD-1 and TIGIT are key regulators of T-cell function in cancer.
  • Their dual blockade shows promise in early clinical trials for cancer patients.
  • Understanding the mechanistic basis of their combined action is critical for optimizing cancer immunotherapy.

Purpose of the Study:

  • To investigate the mechanisms by which PD-1 and TIGIT blockade modulate anti-tumor CD8+ T cells.
  • To elucidate the role of CD226 in the efficacy of PD-1 and TIGIT inhibition.
  • To provide a mechanistic rationale for combining PD-1 and TIGIT blockade in cancer treatment.

Main Methods:

  • Utilized preclinical tumor models to assess the impact of PD-1 and/or TIGIT blockade.
  • Analyzed CD226 expression in non-small cell lung carcinoma (NSCLC) patients treated with anti-PD-L1.
  • Investigated the intracellular signaling pathways of PD-1 and TIGIT in CD8+ T cells.

Main Results:

  • Efficacy of PD-1 or TIGIT inhibition was reduced in CD226-deficient models.
  • CD226 expression correlated with clinical benefit in NSCLC patients treated with atezolizumab.
  • PD-1 blockade inhibited CD226 and CD28 phosphorylation; TIGIT blockade prevented CD226 co-stimulation by blocking PVR interaction.

Conclusions:

  • Optimal anti-tumor CD8+ T-cell responses require combined PD-1 and TIGIT blockade.
  • Restoration of CD226 signaling is essential for effective cancer immunotherapy.
  • This study provides a mechanistic basis for combinatorial PD-1 and TIGIT targeting in clinical settings.
Keywords:
CD226cancer immunotherapycostimulatory receptor TIGITimmune checkpoint blockade

More Related Videos

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells09:32

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

Published on: February 8, 2018

14.9K
Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses10:13

Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses

Published on: May 6, 2019

9.1K

Related Concept Videos

Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
702
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...
6.6K
T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
6.9K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.1K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.0K