NK‐ and T‐cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti‐CTLA‐4 therapy

Abstract

Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK‐cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti‐CTLA‐4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL‐15 stimulation improved NK cell‐mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56bright and CD56dim NK subsets and increased serum concentrations of the cytokines IL‐10, IL‐8 and TNF‐α. After tremelimumab treatment, the ratio between the CD56bright and CD56dim subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM‐3+CD8+ T‐cell frequency, high DNAM‐1+CD56dim NK‐cell frequency and high expression levels of NKp46 on the CD56dim NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.

State of the Art of Natural Killer Cell Imaging: A Systematic Review

“…In general, assays that require a biopsy are less suitable in multimetastatic patients because some lesions might not be accessible. Blood tests may overcome this limitation, as reported by Sottile et al They demonstrated that before anti-CTLA4 therapy, patients affected by malignant mesothelioma showed reduced frequencies of CD56dim and increased frequencies of CD56bright NK cells [90]. After therapy, the ratio reverted back to normal physiological conditions.…”

Natural Killer Cells and Anti-Cancer Therapies: Reciprocal Effects on Immune Function and Therapeutic Response

“…In humans, higher levels of intratumoral NK cells have been correlated with response to anti-CTLA-4 [89,90]. Moreover, in patients with malignant mesothelioma, a perturbation of the PB CD56bright/dim ratio was observed compared to healthy donors, which normalized in favor of the CD56 dim effector NK cells after treatment with tremelimumab, an IgG2 anti-CTLA-4 mAb [91]. Interestingly, in patients with melanoma, lower levels of CD56 dim NK cells were also found, which increased after treatment with ipilimumab, the first approved anti-CTLA-4 mAb [92].…”

The Rise of NK Cell Checkpoints as Promising Therapeutic Targets in Cancer Immunotherapy

“…However, there were still many patients who are nonresponsive to these treatments. However, recent findings indicate that improved survival highly correlates with the frequency of DNAM-1 + CD56 dim NK and NKp46 + CD56 dim NK cells after treatment with anti-CTLA-4 in patients with malignant mesothelioma (125). Hsu and Hodgins et al demonstrated in multiple tumor models that PD-1 is upregulated on the most activated and functionally responsive intratumoral NK cells, suggesting that the efficacy of PD-1 blockade depends in part on inducing an NK cell-based antitumor response (126).…”