Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

Lian, Guang-Yu; Mak, Tony; Yu, Xueqing; Lan, Hui‐Yao

doi:10.3390/ijms23010164

Cited by 20 publications

(17 citation statements)

References 239 publications

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“…Natural killer cells are potential highly effective tumour suppressor immune cells because they can kill cancer cells when activating signals outweigh inhibitory signals. Therefore, various strategies have been used in many clinical and preclinical studies to increase NK cell activity against solid tumours [ 511 ]. Unfortunately, the immunosuppressive TME can also effectively inhibit NK cell function, tipping the balance towards pro-cancer pathways.…”

Section: Resultsmentioning

confidence: 99%

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Starska

2023

Cancers

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Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4+CD25+Foxp3+Tregs), cytotoxic CD3+CD8+ T cells (CTLs) and CD3+CD4+ T helper type 1/2/9/17 (Th1/Th2/Th9/Th17) lymphocytes, T follicular helper cells (Tfh) and CD56dim/CD16bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV+ve (HPV+) and HPV−ve (HPV−) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology.

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Section: Resultsmentioning

confidence: 99%

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Starska

2023

Cancers

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“…TIGIT is a co-inhibitory receptor on the immune cell surface that binds ligands CD155 and CD112 ( 84 ). Different strategies are employed to increase NK cell activity against solid tumors in a number of clinical and pre- clinical studies ( 85 ). Blocking TIGIT interaction with its ligands reduces NK cell exhaustion in vitro and in a murine model ( 86 , 87 ).…”

Section: Discussionmentioning

confidence: 99%

Impaired intratumoral natural killer cell function in head and neck carcinoma

Mele

Pessino²,

Trisolini³

et al. 2022

Front. Immunol.

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Natural killer (NK) cells are emerging as unique players in the immune response against cancer; however, only limited data are available on tumor infiltrating NK cells in head and neck squamous cell carcinoma (HNSCC), one of the most common cancer. Occurrence of HNSCC is closely related to the immune microenvironment, and immunotherapy is increasingly being applied to this setting. However, the limited success of this type of treatment in this tumor calls for further investigation in the field.Surgical HNSSC specimens of 32 consecutive patients were mechanically and enzymatically dissociated. Tumor cells were separated from infiltrating cells by short centrifugation and infiltrating NK cells were phenotypically and functionally characterized by multiple antibody staining and flow cytometry. Tumor infiltrating NK cells in HNSCC showed a peculiar phenotype predominantly characterized by increased NKG2A and reduced Siglec-7, NKG2D, NKp30 and CD16 expression. This phenotype was associated with a decreased ability to perform antibody-dependent cellular cytotoxicity (ADCC). However, NK, CD4 and CD8 shared an increment of glucocorticoid-induced tumor necrosis factor-related (GITR) costimulatory receptor which could be exploited for immunotherapy with agonistic anti-GITR antibodies combined with checkpoint inhibitors.

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“…NK cell triggers inflammatory responses including production of IFNγ and inflammatory cytokines upon activation, which further activates not only innate but also adaptive immunity including cytotoxic T cell (19)(20)(21). As NK cell was activated by ZL-1211 (Fig.…”

Section: Zl-1211 Induces Robust Nk Cell-mediated Inflammationmentioning

confidence: 99%

“…NK cell is an innate immune effector cell that can lyse cancer cells without prior activation (19)(20)(21). Upon activation NK cell releases lysis granules including perforin and granzyme that cooperatively induce cancer cell apoptosis.…”

Section: Authors' Disclosuresmentioning

confidence: 99%

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

Konno

Lin

et al. 2022

Cancer Research Communications

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CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in ~30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in low expressing malignancies. Here, we report that ZL-1211 is a monoclonal antibody targeting CLDN18.2 engineered to promote enhanced antibody-dependent cellular cytotoxicity (ADCC) with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also -low expressing gastric tumor cell lines. Greater anti-tumor efficacy was also observed in mouse xenograft models. Natural killer (NK) cell played critical roles in ZL-1211 efficacy and NK cell depletion abrogated ZL-1211-mediated ADCC activity in vitro. ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL-6 production, and were recruited into tumor microenvironment in patient-derived gastric tumors expressing CLDN18.2 upon ZL-1211 treatment to lyse the tumor cells. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that may not be eligible for treatment with the leading clinical benchmark by inducing enhanced ADCC response and activating NK cells with robust inflammation to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710).

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Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

Cited by 20 publications

References 239 publications

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Impaired intratumoral natural killer cell function in head and neck carcinoma

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

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