Association Between Response to Nivolumab Treatment and Peripheral Blood Lymphocyte Subsets in Patients With Non-small Cell Lung Cancer

Abstract

Immune checkpoint blockade represents a major breakthrough in advanced non-small cell lung cancer (NSCLC) therapy. However, success is limited to a subset of patients and there is a critical need to identify robust biomarkers associated with clinical response. In this study, we assessed whether pre-existing immunological characteristics, as well as immune parameters measured during treatment, might provide such clinical guidance. We studied blood samples collected at baseline and during treatment in a cohort of advanced NSCLC patients (n = 74) treated with nivolumab. Several lymphocyte subsets and biomarkers were then correlated with overall survival (OS) as well as clinical response, assessed using RECIST criteria. We found that patients characterized by longer OS had higher levels of CD3 + , CD4 + , and CD8 + T cells but lower levels of NK cells at baseline. Moreover, that they displayed a statistically significant lower expression of PD-1 on both CD3 + and CD8 + T cells (p = 0.013 and p = 0.033, respectively). The pre-treatment level of exhausted T cells (CD8 + PD1 + Eomes + ) was significantly lower in patients with controlled disease (CD), defined as partial response (PR), and stable disease (SD), compared to those with progressive disease (PD) (p = 0.046). In CD patients, the frequency of exhausted CD8 + T cells further decreased during treatment cycles (p = <0.0001, p = 0.0032, and p = 0.0239, respectively). In conclusion, our results suggest that the distribution of lymphocyte subsets and expression of PD-1 on T cells before treatment may help predict the outcome of anti-PD-1 treatment in NSCLC patients. In addition, assessing the initial levels of exhausted T cells as well as their decrease upon treatment may also predict response and clinical outcome.

Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer

“…During the administration of nivolumab, the circulating NK cell count progressively increased in responders, while remained stable or slightly decreased in non-responders (74). Conversely, Ottonello et al recently reported that a relatively high frequency of baseline NK cells was closely related to poor OS and PFS in NSCLC patients treated with nivolumab (75). These results indicate that the specific function of NK cells in immunotherapy and their potential as biomarkers for predicting response to ICIs require further investigation.…”

Intratumoral versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

“…Conversely, in patients who did not respond to immunotherapy the number of circulating Tregs and NK cells progressively declined [63]. Intriguingly, as indicated above, it has been found that low blood NK cell counts at baseline are a good predictive biomarker for good response in patients treated with nivolumab [67]. However, it should be noted that authors did not differentiate between CD56 bright non-cytotoxic and CD56 dim cytotoxic NK cell subsets and, thus, results are not conclusive regarding NK cells.…”

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

“…Recent studies found that tumor-in ltrating B cells predict a better response to immunotherapy in several kinds of solid tumors, including melanoma, renal cell carcinoma, and sarcoma (27)(28)(29). A retrospective study found that higher baseline blood CD4 + T cells may predict the outcome of anti-PD-1 treatment in patients with advanced non-small cell lung cancer (30). Another study found that blood CD4 + memory T cell subsets played an important role in response to anti-CTLA-4 therapy in melanoma patients (31).…”