Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: finding the missing links in the symbiotic immune-metabolic interplay

Abstract

Individual response to immune checkpoint inhibitors (ICIs) is currently unpredictable in patients with melanoma. Recent findings highlight a striking improvement in the clinical outcomes of overweight/obese patients treated with ICIs, which seems driven, at least in part, by programmed cell death protein 1 (PD-1)-mediated T-cell dysfunction. A putative role of butyrophilins (BTNs) is under investigation as a novel mechanism of cancer immune evasion and obesity-associated inflammation. This study investigates the role of baseline plasma levels of soluble PD-1 (sPD-1), soluble programmed cell death ligand 1 (sPD-L1), BTN2A1 (sBTN2A1), BTN3A1 (sBTN3A1), along with body mass index (BMI), as predictive biomarkers of immunotherapy response in metastatic melanoma patients treated with nivolumab or pembrolizumab as first-line treatment. In all, 41 patients were included in the study. The baseline plasma level of sPD-1 was significantly lower, and the sBTN2A1 was significantly higher, in long-responder patients to nivolumab or pembrolizumab (median sPD-1: 10.3 ng/ml versus 16.6 ng/ml, p = 0.001; median sBTN2A1: 4.4 ng/ml versus 3.77 ng/ml, p = 0.004). Lower levels of sPD-1 and higher levels of sBTN2A1 were also significantly associated with better overall response rate. Notably, when we further stratified the study cohort using BMI along with sPD-1, patients with BMI ⩾ 25 and sPD-1 < 11.24 ng/ml had longer time to treatment failure after PD-1 inhibitor than other subgroups of patients ( p < 0.001). Circulating sPD-1 and sBTN2A1 detection, along with BMI, could give more insights into the immune-metabolic interactions underlying the benefit observed in overweight/obese patients, improving the use of dynamic, noninvasive, biomarkers for patient selection.

Body mass index and baseline platelet count as predictive factors in Merkel cell carcinoma patients treated with avelumab

“…Furthermore, tumor-associated thrombocytosis has been linked to poor clinical outcomes in several cancers, including pancreatic cancer, hepatocellular carcinoma, renal cell carcinoma or glioblastoma (15,(35)(36)(37)(38), and it recently has been significantly associated with a poorer prognosis in lung cancer and melanoma patients receiving immunotherapy (39-41). Rachidi et al (42) showed that platelets can suppress T-cell responses against tumors through the production and activation of immunosuppressive factors, including TGFb, demonstrating how platelet-related TGFb activation contributes dominantly to the immunosuppressive tumor microenvironment.…”

“…On the other hand, all the patients studied were consecutively collected from our single referral Center, thus patients’ data, although retrospective, should be homogenous, limiting possible biases. In addition, BMI is not a perfect assessment of obesity because it cannot distinguish muscle from body fat ( 43 ). Accordingly, more specific body fat assessment methods should be used in future prospective studies on larger cohorts.…”