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Exploring natural killer cell immunology as a therapeutic strategy in lung cancer.

ABSTRACT: Cytotoxic immune cells are key in the control of tumor development and progression. Natural killer (NK) cells are the cytotoxic arm of the innate immune system with the capability to kill tumor cells and surveil tumor cell dissemination. As such, the interest in harnessing NK cells in tumor control is increasing in many solid tumor types, including lung cancer. Here, we review the pre-clinical models used to unveil the role of NK cells in immunosurveillance of solid tumors and highlight measures to enhance NK cell activity. Importantly, the development of NK immunotherapy is rapidly evolving. Enhancing the NK cell response can be achieved using two broad modalities: enhancing endogenous NK cell activity, or performing adoptive transfer of pre-activated NK cells to patients. Numerous clinical trials are evaluating the efficacy of NK cell immunotherapy in isolation or in combination with standard treatments, with encouraging initial results. Pre-clinical studies and early phase clinical trials suggest that patients with solid tumors, including lung cancer, have the potential to benefit from recent developments in NK cell immunotherapy.

SUBMITTER: Hess JB

PROVIDER: S-EPMC8264324 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Exploring natural killer cell immunology as a therapeutic strategy in lung cancer.

Hess Jonas B JB Sutherland Kate D KD Best Sarah A SA

Translational lung cancer research 20210601 6

Cytotoxic immune cells are key in the control of tumor development and progression. Natural killer (NK) cells are the cytotoxic arm of the innate immune system with the capability to kill tumor cells and surveil tumor cell dissemination. As such, the interest in harnessing NK cells in tumor control is increasing in many solid tumor types, including lung cancer. Here, we review the pre-clinical models used to unveil the role of NK cells in immunosurveillance of solid tumors and highlight measures ...[more]

PMID: 34295678

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Project description:Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatments over the last 10 years, with even increasing indications in many neoplasms. Non-small cell lung cancer (NSCLC) is considered highly immunogenic, and ICIs have found a wide set of applications in this area, in both early and advanced lines of treatment, significantly changing the prognosis of these patients. Unfortunately, not all patients can benefit from the treatment, and resistance to ICIs can develop at any time. In addition to T lymphocytes, which are the major target, a variety of other cells present in the tumor microenvironment (TME) act in a complex cross-talk between tumor, stromal, and immune cells. An imbalance between activating and inhibitory signals can shift TME from an "anti-" to a "pro-tumorigenic" phenotype and vice versa. Natural killer cells (NKs) are able to recognize cancer cells, based on MHC I (self and non-self) and independently from antigen presentation. They represent an important link between innate and adaptive immune responses. Little data are available about the role of pro-inflammatory NKs in NSCLC and how they can influence the response to ICIs. NKs express several ligands of the checkpoint family, such as PD-1, TIGIT, TIM-3, LAG3, CD96, IL1R8, and NKG2A. We and others have shown that TME can also shape NKs, converting them into a pro-tumoral, pro-angiogenic "nurturing" phenotype through "decidualization." The features of these NKs include expression of CD56, CD9, CD49a, and CXCR3; low CD16; and poor cytotoxicity. During ICI therapy, tumor-infiltrating or associated NKs can respond to the inhibitors or counteract the effect by acting as pro-inflammatory. There is a growing interest in NKs as a promising therapeutic target, as a basis for adoptive therapy and chimeric antigen receptor (CAR)-NK technology. In this review, we analyzed current evidence on NK function in NSCLC, focusing on their possible influence in response to ICI treatment and resistance development, addressing their prognostic and predictive roles and the rationale for exploiting NKs as a tool to overcome resistance in NSCLC, and envisaging a way to repolarize decidual NK (dNK)-like cells in lung cancer.

Project description:Objective: Neoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer (NSCLC), yet its real-world implementation is often challenged by surgical delays, cancellations, immune-related fibrosis, and increased postoperative complications. Smokers with NSCLC, despite being at higher risk for postoperative complications, have enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could inform treatment strategies. Methods: Single-cell RNA sequencing was performed on 61 lung samples from non-smokers, smokers, and patients with chronic obstructive pulmonary disease (COPD), as well as 8 invasive lung adenocarcinomas, to define smoking-related immune signatures. Using RNA sequencing data from 102 resected NSCLC and 24 NSCLC patients treated with neoadjuvant chemoimmunotherapy, we conducted in silico deconvolution to evaluate associations between cellular composition and clinical outcomes. Results: Among 140 lung cellular phenotypes, two natural killer (NK) cell subsets were strongly associated with smoking and COPD severity. “Stress-responsive NK (NKSR)” cells exhibited immature features and cytokine-responsive signatures. “Exhausted NK (NKExh)” cells showed mature features and elevated multiple immune checkpoint expression (PDCD1, TIGIT, and LAG3). Abundant intratumoral NKSR cells were associated with significantly improved survival after surgery, particularly in current smokers. Conversely, tumors with low NKSR and high NKExh cell profiles were associated with better responses to neoadjuvant chemoimmunotherapy. Conclusions: Tumor-infiltrating NK cell phenotyping may aid in therapeutic stratification in smokers with NSCLC. NKSR cell preservation predicts favorable outcomes with upfront surgery, while NKExh cell enrichment indicates greater benefit from neoadjuvant chemoimmunotherapy. These profiles may help optimize treatment by balancing therapeutic benefit and risk.

Dataset Information

Exploring natural killer cell immunology as a therapeutic strategy in lung cancer.

Publications

Exploring natural killer cell immunology as a therapeutic strategy in lung cancer.

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