Intratumoral cDC1–T cell clusters serve as sites of local costimulation to enhance CTL-mediated tumor rejection

T cells are essential for antitumor immunity, but their ability to eliminate tumors depends on interactions with type 1 conventional dendritic cells (cDC1s). cDC1s are known for cross-presenting tumor-derived antigens in lymph nodes to prime T cells, but their role within tumors remains less well understood. Here, we use a tumor array model to investigate how cDC1-T cell interactions influence immune responses and tumor fate. We show that the spatial distribution of both cDC1s and T cells determines whether a tumor can be rejected. We defined three immunotypes based on the spatial distribution of T cells and cDC1s: T cell-inflamed/dendritic cell-inflamed (TC-In/DC-In) tumors, where T cells and cDC1s coinfiltrate the tumor; T cell-inflamed/dendritic cell-excluded (TC-In/DC-Ex) tumors, where T cells infiltrate but cDC1s remain at the periphery; and T cell-excluded/dendritic cell-excluded (TC-Ex/DC-Ex) tumors, which lack both cDC1 and T cell infiltration. TC-In/DC-In tumors are most likely to undergo rejection, whereas TC-In/DC-Ex tumors persist despite T cell infiltration. Within TC-In/DC-In tumors, cDC1s interact directly with T cells, upregulate costimulatory molecules, and sustain effector T cell responses, while cDC1s in TC-In/DC-Ex tumors express higher migration-associated genes, suggesting they may exit the tumor. We further show that chemokine modulation, particularly through CXCL9, CCL5, and XCL1, can reshape immune infiltration patterns to promote intratumoral cDC1-T cell clustering and improve tumor rejection. These findings reveal an important role of cDC1 in sustaining effective antitumor immunity and highlight spatially organized cDC1-T cell clusters as critical hubs for local T cell activation.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-11-02
DOI
https://doi.org/10.1073/pnas.2621357123
Citations
2
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
2.32

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article

Intratumoral cDC1–T cell clusters serve as sites of local costimulation to enhance CTL-mediated tumor rejection

Justin Tyler Gibson, Shomyseh Sanjabi, Markus K. Brown, Anthony C. Antonelli et al.
2 citations
Proceedings of the National Academy of Sciences
Immunotherapy and Immune Responses
2.32
article

Intratumoral cDC1–T cell clusters serve as sites of local costimulation to enhance CTL-mediated tumor rejection

Justin Tyler Gibson, Shomyseh Sanjabi, Markus K. Brown, Anthony C. Antonelli, Karl L. Banta, Geraldine A. Strasser, Christine Moussion, Jeanne Cheung, Ximo Pechuan-Jorge, Camille-Charlotte Balança, Jérémie Decalf, Vincent Rouilly, Aditya A. Anand, Rosa Barreira da Silva, Caleb K. Chan, Lélia Delamarre, Elisa Penna, Sandra Rost, Inés Marín, Catherine B. Carbone, Shiuh-Ming Luoh, Ira Mellman, Ellen Duong, Guadalupe Ortiz-Muñoz, Ying Zhu, Jian Jiang, James Ziai, Yuxin Liang, Anugraha Rajagopalan, Linda Rangell, Amanda Lorentzian, Rajiv Jesudason, Kathryn Geiger-Schuller, Shannon J. Turley
article en
2 citations

Abstract

T cells are essential for antitumor immunity, but their ability to eliminate tumors depends on interactions with type 1 conventional dendritic cells (cDC1s). cDC1s are known for cross-presenting tumor-derived antigens in lymph nodes to prime T cells, but their role within tumors remains less well understood. Here, we use a tumor array model to investigate how cDC1-T cell interactions influence immune responses and tumor fate. We show that the spatial distribution of both cDC1s and T cells determines whether a tumor can be rejected. We defined three immunotypes based on the spatial distribution of T cells and cDC1s: T cell-inflamed/dendritic cell-inflamed (TC-In/DC-In) tumors, where T cells and cDC1s coinfiltrate the tumor; T cell-inflamed/dendritic cell-excluded (TC-In/DC-Ex) tumors, where T cells infiltrate but cDC1s remain at the periphery; and T cell-excluded/dendritic cell-excluded (TC-Ex/DC-Ex) tumors, which lack both cDC1 and T cell infiltration. TC-In/DC-In tumors are most likely to undergo rejection, whereas TC-In/DC-Ex tumors persist despite T cell infiltration. Within TC-In/DC-In tumors, cDC1s interact directly with T cells, upregulate costimulatory molecules, and sustain effector T cell responses, while cDC1s in TC-In/DC-Ex tumors express higher migration-associated genes, suggesting they may exit the tumor. We further show that chemokine modulation, particularly through CXCL9, CCL5, and XCL1, can reshape immune infiltration patterns to promote intratumoral cDC1-T cell clustering and improve tumor rejection. These findings reveal an important role of cDC1 in sustaining effective antitumor immunity and highlight spatially organized cDC1-T cell clusters as critical hubs for local T cell activation.

Proceedings of the National Academy of SciencesVol. 123(45)
Genentech (US), Revolution Medicines (United States) (US), Parker Institute for Cancer Immunotherapy (US), Kite Pharma (United States) (US), Seattle Children's Research Institute (US)
Genentech
Good health and well-being
Openalex Percentile: Top 20%
Immunotherapy and Immune Responses
2.32
DOIOpen Access PDFOpenAlex
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