Increased diversity with reduced "diversity evenness" of tumor infiltrating T-cells for the successful cancer immunotherapy.

Abstract

To facilitate the optimization of cancer immunotherapy lacking immune-related adverse events, we performed TCR repertoire analysis of tumor-infiltrating CD8+ T-cells in B16 melanoma-bearing mice receiving anti-PD-1, anti-CTLA-4, anti-4-1BB, anti-CD4 or a combination of anti-PD-1 and 4-1BB antibodies. Although CD8+ T-cells in the tumor were activated and expanded to a greater or lesser extent by these therapies, tumor growth suppression was achieved only by anti-PD-1, anti-PD-1/4-1BB combined, or by anti-CD4 treatment, but not by anti-CTLA-4 or anti-4-1BB monotherapy. Increased CD8+ T cell effector function and TCR diversity with enrichment of certain TCR clonotypes in the tumor was associated with anti-tumor effects. In contrast, polyclonal activation of T-cells in the periphery was associated with tissue damage. Thus, optimal combination therapy increases TCR diversity with extended activation of selective CD8+ T-cells specifically in the tumor but not in the periphery. Incorporation of the concept of evenness for the TCR diversity is proposed.

• Authors: Akihiro Hosoi, Kazuyoshi Takeda, Koji Nagaoka, Tamaki Iino, Hirokazu Matsushita, Satoshi Ueha, Shin Aoki, Kouji Matsushima, Masato Kubo, Teppei Morikawa, Kazutaka Kitaura, Ryuji Suzuki, Kazuhiro Kakimi
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 1058 (01 18 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29348598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Immunological
• Biomarkers, Tumor
• Receptors, Antigen, T-Cell

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Biomarkers, Tumor
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Humans
• Immunomodulation
• Immunotherapy (adverse effects, methods)
• Lymphocyte Activation (immunology)
• Lymphocyte Count
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism, pathology)
• Melanoma, Experimental
• Mice
• Mice, Transgenic
• Neoplasms (immunology, metabolism, pathology, therapy)
• Receptors, Antigen, T-Cell (metabolism)
• T-Cell Antigen Receptor Specificity
• T-Lymphocyte Subsets (immunology, metabolism, pathology)
• Tumor Burden (drug effects)