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

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, Dong-Won; Kim, Wun-Jae; Yun, Seok Joong; Shin, Eui‐Cheol

doi:10.1016/j.canlet.2020.11.035

Cited by 45 publications

(37 citation statements)

References 46 publications

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“…As shown in figure 4G , one CD4 + Tex cell population (C11) and six CD8 + Tex cell populations (C0, C1, C5, C6, C8, and C10) expressed high levels of the transcription factors Ikzf2 and Tox , both of which are well-known genes associated with T cell exhaustion. 32 33 Additionally, DEG analysis of the CD4 + Tex population revealed the presence of significantly upregulated inhibitory molecules such as Ikzf2, Lag3, Havcr2, and Entpd1 in the C11 cluster ( figure 4H, I ). 34 Our volcano blot ( figure 4I ) revealed that gene expression was significantly altered in response to AB680 treatment and PD-1 blockade in CD4 + Tex cells (C11).…”

Section: Resultsmentioning

confidence: 98%

“…Importantly, we observed a relatively low level of CD69 expression in AB680-treated CD8 + effector T cell population (C9) compared with that in the PD-1 blocker-treated group ( figure 5H, I ). Interestingly, AB680 treatment triggered the expression of Tox, a process that is well known to be indicative of T cell exhaustion, 32 33 in the CD8 + effector T cell population (C9). This suggested that AB680 treatment, and not PD-1 blockade, triggered the effector function of exhausted CD8+ T cells.…”

Section: Resultsmentioning

confidence: 99%

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Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

Kim

Min

Jang

et al. 2021

J Immunother Cancer

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BackgroundAlthough cancer immunotherapy is one of the most effective advanced-stage cancer therapies, no clinically approved cancer immunotherapies currently exist for colorectal cancer (CRC). Recently, programmed cell death protein 1 (PD-1) blockade has exhibited clinical benefits according to ongoing clinical trials. However, ongoing clinical trials for cancer immunotherapies are focused on PD-1 signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab. In this study, we focused on revealing the distinct response mechanism for the potent CD73 ectoenzyme selective inhibitor AB680 as a promising drug candidate that functions by blocking tumorigenic ATP/adenosine signaling in comparison to current therapeutics that block PD-1 to assess the value of this drug as a novel immunotherapy for CRC.MethodsTo understand the distinct mechanism of AB680 in comparison to that of a neutralizing antibody against murine PD-1 used as a PD-1 blocker, we performed single-cell RNA sequencing of CD45+ tumor-infiltrating lymphocytes from untreated controls (n=3) and from AB680-treated (n=3) and PD-1-blockade-treated murine CRC in vivo models. We also used flow cytometry, Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) models, and in vitro functional assays to validate our new findings.ResultsWe initially observed that the expressions of Nt5e (a gene for CD73) and Entpd1 (a gene for CD39) affect T cell receptor (TCR) diversity and transcriptional profiles of T cells, thus suggesting their critical roles in T cell exhaustion within tumor. Importantly, PD-1 blockade significantly increased the TCR diversity of Entpd1-negative T cells and Pdcd1-positive T cells. Additionally, we determined that AB680 improved the anticancer functions of immunosuppressed cells such as Treg and exhausted T cells, while the PD-1 blocker quantitatively reduced Malat1high Treg and M2 macrophages. We also verified that PD-1 blockade induced Treg depletion in AOM/DSS CRC in vivo models, and we confirmed that AB680 treatment caused increased activation of CD8+ T cells using an in vitro T cell assay.ConclusionsThe intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

Kim

Min

Jang

et al. 2021

J Immunother Cancer

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“…Second, exhausted CD8 + T cells are transcriptionally altered (Khan et al, 2019). Various transcription factors responsible for T cell exhaustion (e.g., Eomes, TOX, and Blimp1) are expressed in exhausted CD8 + T cells (Shin et al, 2009;Buggert et al, 2014;Wang et al, 2019a;Khan et al, 2019;McLane et al, 2019;Kim et al, 2020;Han et al, 2021). Eventually, exhausted CD8 + T cells are unable to respond to tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy

Kim

2021

Front. Cell Dev. Biol.

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In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8+ T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8+ T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8+ T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.

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“…In patients with bladder cancer, TIGIT expression has also been predominantly co-expressed on PD-1 + tumor-infiltrating CD8 + T-cells. Moreover, TIGIT blockade can improve the efficacy of anti-PD-1 therapy and promote the stimulation of tumor-infiltrating CD8 + T-cells in patients with bladder cancer [ 42 ]. Besides, TIGIT/PD-1 dual blockade has remarkably improved anti-tumoral immune responses and promoted tumor rejection in lymphoma animal models [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers

Hosseinkhani

Baradaran

Jafarabadi

et al. 2021

IJMS

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Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11–1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43–3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36–2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10–2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

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

Cited by 45 publications

References 46 publications

Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers

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