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

Hye Sook Han; Seongju Jeong; Hyunglae Kim; Hyung-Don Kim; A Reum Kim; Minsuk Kwon; Su-Hyung Park; Chang Gok Woo; Hee Kyung Kim; Ki Hyeong Lee; Sung Pil Seo; Ho Won Kang; Won Tae Kim; Wun-Jae Kim; Seok Joong Yun; Eui-Cheol Shin

doi:10.1016/j.canlet.2020.11.035

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

Cancer Lett. 2021 Feb 28:499:137-147. doi: 10.1016/j.canlet.2020.11.035. Epub 2020 Nov 27.

Authors

Hye Sook Han¹, Seongju Jeong², Hyunglae Kim², Hyung-Don Kim², A Reum Kim², Minsuk Kwon², Su-Hyung Park², Chang Gok Woo³, Hee Kyung Kim⁴, Ki Hyeong Lee¹, Sung Pil Seo⁵, Ho Won Kang⁶, Won Tae Kim⁶, Wun-Jae Kim⁶, Seok Joong Yun⁷, Eui-Cheol Shin⁸

Affiliations

¹ Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea; Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea.
² Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
³ Department of Pathology, Chungbuk National University Hospital, Cheongju, Republic of Korea.
⁴ Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea.
⁵ Department of Urology, Chungbuk National University Hospital, Cheongju, Republic of Korea.
⁶ Department of Urology, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.
⁷ Department of Urology, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Republic of Korea. Electronic address: [email protected].
⁸ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. Electronic address: [email protected].

PMID: 33249194
DOI: 10.1016/j.canlet.2020.11.035

Abstract

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-1^highCD8⁺ 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-1^highTOX⁺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.

Keywords: Bladder cancer; CD8(+) T cell; PD-1; TIGIT; TOX.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Carcinoma, Transitional Cell / immunology
Carcinoma, Transitional Cell / pathology
Carcinoma, Transitional Cell / therapy*
Chemotherapy, Adjuvant / methods
Cystectomy
Drug Synergism
Female
High Mobility Group Proteins / metabolism
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Lymphocyte Activation / drug effects
Lymphocytes, Tumor-Infiltrating / drug effects
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Male
Middle Aged
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
Tumor Cells, Cultured
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology
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*

Substances

High Mobility Group Proteins
Immune Checkpoint Inhibitors
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Receptors, Immunologic
TIGIT protein, human
TOX protein, human