Dendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response.

Abstract

The development of the most successful cancer immunotherapies in solid tumors, immune-checkpoint blockade, has focused on factors regulating T-cell activation. Until recently, the field has maintained a predominately T-cell centric view of immunotherapy, leaving aside the impact of innate immunity and especially myeloid cells. Dendritic cells (DC) are dominant partners of T cells, necessary for initiation of adaptive immune responses. Emerging evidence supports a broader role for DCs in tumors including the maintenance and support of effector functions during T-cell responses. This relationship is evidenced by the association of activated DCs with immune-checkpoint blockade responses and transcriptional analysis of responding tumors demonstrating the presence of type I IFN transcripts and DC relevant chemokines. T-cell-inflamed tumors preferentially respond to immunotherapies compared with non-T-cell-inflamed tumors and this model suggests a potentially modifiable spectrum of tumor microenvironmental immunity. Although host and commensal factors may limit the T-cell-inflamed phenotype, tumor cell intrinsic factors are gaining prominence as therapeutic targets. For example, tumor WNT/β-catenin signaling inhibits production of chemokine gradients and blocking DC recruitment to tumors. Conversely, mechanisms of innate immune nucleic acid sensing, normally operative during pathogen response, may enhance DC accumulation and make tumors more susceptible to cancer immunotherapy. Elucidating mechanisms whereby DCs infiltrate and become activated within tumors may provide new opportunities for therapeutic intervention. Conceptually, this would facilitate conversion of non-T-cell-inflamed to T-cell-inflamed states or overcome secondary resistance mechanisms in T-cell-inflamed tumors, expanding the proportion of patients who benefit from cancer immunotherapy.

• Authors: Christopher S Garris, Jason J Luke
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 15 Pg. 3901-3907 (08 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32332013 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Review)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Immune Checkpoint Inhibitors

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Communication (immunology)
• Dendritic Cells (drug effects, immunology)
• Disease Models, Animal
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Immunotherapy (methods)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Neoplasms (drug therapy, immunology, pathology)
• T-Lymphocytes (drug effects, immunology)
• Tumor Microenvironment (drug effects, immunology)
• Wnt Signaling Pathway (drug effects, immunology)