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Gregory J. Riely, MD, PhD


Lack of Success for Immunotherapy in Lung Cancer: Could the Reason Be Ineffective Priming of Cytotoxic T Lymphocytes?

By: Amy MacDonald, MS
Posted: Thursday, April 6, 2023

Appropriately activated cytotoxic CD8-positive T cells are essential for antitumor immunity. T-cell activation trajectories are established in tumor-draining lymph nodes through the complex signaling that native T cells receive from conventional type 1 dendritic cells. Functionality of committed antitumor T cells depends not only on receiving tumor antigen from dendritic cells, but also on the abundance, timing, and content of the molecular signaling the dendritic cells themselves receive.

Stefani Spranger, PhD, of the Massachusetts Institute of Technology (MIT), Boston, and colleagues investigated the causes of ineffective antitumor T-cell priming in lung cancer by examining the microenvironment where activation occurs. Published in Immunity, their data showed that tissue-specific activation of T-regulatory cells, in the presence of excess interferon gamma, may suppress dendritic cell–mediated cytotoxic T-cell activation.

“There is a functional difference between the T-cell responses that are mounted in the different lymph nodes. We’re hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung tumor–targeting T cells,” Dr. Spranger stated in an MIT press release.

Using various murine models, the researchers compared T-cell activation responses to tumors growing orthotopically in the lungs with those growing subcutaneously in the flanks. They found that T-regulatory cells (induced by abundant interferon-gamma) in the lung tumor–draining (mediastinal) lymph nodes, but not the flank (inguinal) nodes, suppressed dendritic cell regulatory signals. Of note, antibody-mediated blockade of this excess interferon-gamma restored cytotoxic T-cell activation in this model, providing a potential new therapeutic target for lung cancer research.

Disclosure: For full disclosures of the study authors, visit

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