Research thoughts by:

Ang Cui

Deciphering lymph node cytokine activities in cancer immunotherapy

10/5/2025

Despite advances in immunotherapy, many cancer patients do not yet respond to immune checkpoint blockade such as anti-PD-1, and there is a significant challenge in understanding the mechanisms of resistance and predicting which patients are more likely to benefit from such therapies. Cytokines, extracellular signaling molecules of the immune system, play a critical role in immune activation, potentially mediating an effective or ineffective immune response to immunotherapies. However, due to the large number of cytokines and cell types, as well as the complex cellular responses to diverse cytokines, it has been challenging to systematically decode cellular responses to cytokines in responders vs. non-responders in cancer patients. The lymph nodes are key organs where anti-tumor immunity develops and are routinely biopsied for cancer staging purposes. Therefore, understanding cytokine activities in lymph nodes holds tremendous potential for deciphering mechanisms of anti-cancer immunity and predicting treatment response. Recently, we built the Immune Dictionary (Cui et al., Nature, 2024), where we systematically measured the single-cell transcriptomic responses of >17 immune cell types in response to each of 86 cytokines in murine lymph nodes in vivo, providing a large-scale compendium of cell-type-specific cytokine signatures for >1,400 cytokine-cell type combinations. Based on the dictionary, we created its companion software, Immune Response Enrichment Analysis (IREA), enabling automated assessment of cytokine activities from gene expression data. This creates a unique opportunity to understand cytokine responses in lymph nodes in cancer immunotherapy, which may offer unprecedented mechanistic and predictive insights into cancer immunotherapy responsiveness.

My Karin Grunebaum Cancer Research Foundation Faculty Fellowship project leverages our Immune Dictionary to investigate cytokine activities in tumor-sentinel lymph nodes of responder and non-responder populations to anti-PD-1 therapy, with the goal of uncovering cytokine pathways that mediate effective anti-cancer immunity and establishing a novel framework for predicting patient responses to anti-PD-1 therapy at the time of diagnosis.