CD4 <sup>+</sup> T cells impair tumor growth through IL-3 and TNF-dependent vascular damage
Abstract
Most cancer immunotherapy strategies are focused on direct tumor killing by immune cells, especially T lymphocytes. Clinical and conceptual limitations of these approaches create a need for additional strategies. We identified a tumor stroma–targeting mechanism in which tumor antigen–specific CD4 + T cells inhibit tumor growth through myeloid cell and tumor necrosis factor (TNF)–dependent vascular damage. Multiplex immunofluorescence and single-cell and tissue transcriptomics showed that CD4 + T cells trigger the formation of perivascular myeloid cell clusters containing “classically activated” macrophages that produce TNF in response to T cell–derived interleukin-3. TNF causes intratumoral endothelial damage and blood supply disruption, which are associated with localized tumor cell death. Thus, intratumoral antigen-triggered T cell activation can mediate antitumor effects without direct recognition of living tumor cells, thereby avoiding many of the inhibitory mechanisms that limit anti-tumor immunity.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (14)
Qiaoshi Lian
Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Jia Nie
Jatinder Singh
Single Cell Analysis Facility, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Qiang Chen
Jennifer Matta
Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Waipan Chan
Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Mariah Balmaceno-Criss
Laboratory of Immune Cell Biology and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Melanie S. Vacchio
Laboratory of Immune Cell Biology and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Weiming Yu
Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Alexander D. Clark
Laboratory of Immune Cell Biology and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Elijah Edmondson
Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Michael C. Kelly
Single Cell Analysis Facility, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Ronald N. Germain
Rémy Bosselut