TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer

• Published in: Cancer letters 2021-02, Vol.499, p.137-147
• Main Authors: Han, Hye Sook, Jeong, Seongju, Kim, Hyunglae, Kim, Hyung-Don, Kim, A.Reum, Kwon, Minsuk, Park, Su-Hyung, Woo, Chang Gok, Kim, Hee Kyung, Lee, Ki Hyeong, Seo, Sung Pil, Kang, Ho Won, Kim, Won Tae, Kim, Wun-Jae, Yun, Seok Joong, Shin, Eui-Cheol
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies; Antigens; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Bladder cancer; Cancer therapies; Carcinoma, Transitional Cell - immunology; Carcinoma, Transitional Cell - pathology; Carcinoma, Transitional Cell - therapy; CD8 antigen; CD8+ T cell; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell death; Chemotherapy, Adjuvant - methods; Cystectomy; Cytokines; Drug Synergism; Female; Flow cytometry; High mobility group proteins; High Mobility Group Proteins - metabolism; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunoglobulins; Immunotherapy; Ligands; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Middle Aged; PD-1; PD-1 protein; Primary Cell Culture; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Prospective Studies; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; TIGIT; TOX; Transcription factors; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor necrosis factor-TNF; Tumor-infiltrating lymphocytes; Urinary Bladder - drug effects; Urinary Bladder - immunology; Urinary Bladder - pathology; Urinary Bladder - surgery; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - therapy; Urothelial cancer
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.11.035

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients. •PD-1highTOX+CD8+ TILs are the most terminally exhausted CD8+ TILs in bladder cancer.•TIGIT is the most commonly co-expressed ICR in PD-1+CD8+ TILs in bladder cancer.•Anti-TIGIT enhances the anti-PD-1-induced reinvigoration of exhausted CD8+ TILs.