Lack of reliable predictive biomarkers is a major limitation of combination therapy with chemotherapy and anti–programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) therapy (chemo-immunotherapy). We previously observed that the increase of peripheral blood CD8+ T cells expressing CX3CR1, a marker of differentiation, correlates with response to anti–PD-1 therapy; however, the predictive and prognostic value of T-cell CX3CR1 expression during chemo-immunotherapy is unknown. Here, we evaluated the utility of circulating CX3CR1+CD8+ T cells as a predictive correlate of response to chemo-immunotherapy in patients with non–small cell lung cancer (NSCLC). At least 10% increase of the CX3CR1+ subset in circulating CD8+ T cells from baseline (CX3CR1 score) was associated with response to chemo-immunotherapy as early as 4 weeks with 85.7% overall accuracy of predicting response at 6 weeks. Furthermore, at least 10% increase of the CX3CR1 score correlated with substantially better progression-free (P = 0.0051) and overall survival (P = 0.0138) on Kaplan–Meier analysis. Combined single-cell RNA/T-cell receptor (TCR) sequencing of circulating T cells from longitudinally obtained blood samples and TCR sequencing of tumor tissue from the same patient who received a long-term benefit from the treatment demonstrated remarkable changes in genomic and transcriptomic signatures of T cells as well as evolution of TCR clonotypes in peripheral blood containing highly frequent tumor-infiltrating lymphocyte repertoires overexpressing CX3CR1 early after initiation of the treatment despite stable findings of the imaging study. Collectively, these findings highlight the potential utility of T-cell CX3CR1 expression as a dynamic blood-based biomarker during the early course of chemo-immunotherapy and a marker to identify frequent circulating tumor-infiltrating lymphocyte repertoires.Significance: Current approaches to combined chemotherapy and anti-PD-1/PD-L1 therapy (chemo-immunotherapy) for patients with NSCLC are limited by the lack of reliable predictive biomarkers. This study shows the utility of T-cell differentiation marker, CX3CR1, as an early on-treatment predictor of response and changes in genomic/transcriptomic signatures of circulating tumor-infiltrating lymphocyte repertoires in patients with NSCLC undergoing chemo-immunotherapy.

Corticosteroids are frequently prescribed to patients with non–small cell lung cancer (NSCLC) for palliation of cancer-related symptoms; however, the potential impact of baseline steroid use on immune checkpoint inhibitor (ICI) therapy and its underlying mechanisms remain unclear. In this study, we evaluated clinical outcomes of 277 patients with NSCLC treated with ICI therapy at two academic institutions. Twenty-one patients (8%) were taking steroids at the start of ICIs. Patients on baseline steroids had a lower overall response rate with markedly shorter progression-free survival and overall survival compared with those not receiving steroids. In multivariate analysis, steroid use was the only significant independent risk factor for disease progression and mortality in both independent cohorts, Roswell Park Comprehensive Cancer Center (n = 88) and University of Southern California (n = 189). A baseline peripheral blood neutrophil-to-lymphocyte ratio <5 was a strong prognostic indicator; however, the prognostic value of neutrophil-to-lymphocyte ratio was absent in patients receiving steroids. Additionally, the baseline frequency of circulating CX3CR1+CD8+ T cells was substantially lower in patients on steroids. Using a bedside-to-bench approach, we found that concurrent steroid use significantly decreased antitumor efficacy of anti–PD-1 therapy and attenuated the increase of CX3CR1+CD8+ T cells in mice bearing MC38 tumors whereas discontinuation of steroid at the start of treatment did not make a negative impact on survival. Collectively, baseline steroid use was associated with worse outcomes and decreased frequency of circulating differentiated effector T cells in patients with NSCLC. Caution should be taken when interpreting the results from circulating immune-related biomarkers in patients on steroids. Significance: The impact of corticosteroids, widely prescribed for palliation of cancer-related symptoms, on ICI therapy remains unclear. This study shows that baseline steroid use is a negative independent prognostic factor in patients with NSCLC undergoing ICI therapy and provides insights into the decreased T-cell effector differentiation and utility of predictive blood-based markers by steroids.

Gastroesophageal (GE) junction adenocarcinoma is an aggressive malignancy of growing incidence and is associated with public health issues such as obesity and GERD. Management has evolved over the last two decades to incorporate a multidisciplinary approach, including endoscopic intervention, neoadjuvant chemotherapy/chemoradiation, and minimally invasive or more limited surgical approaches. Surgical approaches include esophagectomy, total gastrectomy, and, more recently, proximal gastrectomy. This review analyzes the evidence for and applicability of these varied approaches in management, as well as areas of continued controversy and investigation.