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The Intrinsic Apoptotic Pathway

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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...

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The Extrinsic Apoptotic Pathway

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Related Experiment Video

Updated: Jan 4, 2026

Author Spotlight: Magnetic Fluorescent Bead-Based Dual-Reporter Flow Analysis of PDL1-Vaxx Peptide Vaccine-Induced Antibody Blockade of the PD-1/PD-L1 Interaction

Author Spotlight: Magnetic Fluorescent Bead-Based Dual-Reporter Flow Analysis of PDL1-Vaxx Peptide Vaccine-Induced Antibody Blockade of the PD-1/PD-L1 Interaction

Published on: July 7, 2023

Lesion-Level Response Dynamics to Programmed Cell Death Protein (PD-1) Blockade.

Juan C Osorio¹, Kathryn C Arbour^1,2, Dung T Le³

¹Memorial Sloan Kettering Cancer Center, New York, NY.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

|November 2, 2019

Summary

Immune checkpoint inhibitor therapy, specifically programmed cell death protein 1 (PD-1) blockade, shows uniform response across metastases, suggesting peripheral immunity is key. Progression patterns reveal heterogeneity, highlighting local factors in immunotherapy resistance.

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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Area of Science:

Immunology
Oncology
Medical Imaging

Background:

Programmed cell death protein 1 (PD-1) blockade response is often attributed to reinvigorated tumor-infiltrating lymphocytes.
Recruited antitumor immunity from the periphery may also significantly contribute to treatment response.
Assessing individual metastasis response dynamics can elucidate systemic and local factors in immunotherapy response and resistance.

Purpose of the Study:

To evaluate the response dynamics of individual metastases in patients receiving PD-1 monotherapy.
To investigate the role of peripheral immunity versus local tumor factors in response to PD-1 blockade.
To correlate metastasis response patterns with clinical outcomes in non-small-cell lung cancer (NSCLC) and mismatch repair deficiency (MMRD) carcinoma.

Main Methods:

Retrospective analysis of patients with metastatic NSCLC or MMRD carcinoma treated with PD-1 monotherapy.
Quantification of absolute and percent change of target lesions using RECIST criteria at serial CT scans.
Classification of progression patterns as systemic or mixed, and correlation with progression-free and overall survival.

Main Results:

Individual lesion responses aligned with overall patient response (85% NSCLC, 93% MMRD).
Responding lesions showed synchronous response (73% NSCLC, 76% MMRD), with deeper responses correlating to improved survival.
Mixed progression was common (45% NSCLC, 53% MMRD) and associated with improved survival compared to systemic progression.

Conclusions:

Uniform temporal-spatial response patterns across metastases suggest a significant role for peripheral, clonally directed antitumor immunity in PD-1 blockade response.
Heterogeneous progression patterns indicate the clinical importance of local tumor features and intertumoral heterogeneity in immunotherapy resistance.