Lung cancer is the first and second cause of cancer mortality in men and women, respectively, thus representing an important health problem that needs new therapeutic solutions. Immune checkpoint inhibitors (ICI), consisting in neutralizing antibodies (Ab) targeting co-inhibitory molecules to restore T cell activation, have revolutionized cancer therapy. Anti-PD-1 Abs have emerged as powerful weapons. Durable objective responses following anti-PD1 Ab therapy in patients with non-small-cell lung cancer (NSLC), accompanied by extended overall survival compared with conventional therapies, supported recent regulatory approvals by the US Food and Drug Administration for the use of nivolumab and pembrolizumab, two different anti-PD1 Abs, in these indications. Nevertheless, patients treated with ICI can develop immune related adverse events, such as dermatological toxicities, as a consequence of counteracting T cell inhibition. We report here a case of sarcoidosis in a 56-year-old patient with unresectable NSLC and treated with nivolumab.

PD-1 and PD-1 ligands expression was assessed on peripheral blood mononuclear cells (PBMC) of the patient, at different time-points (days 42, 56, 147 and 251) after nivolumab arrest.

Nivolumab was initiated to treat a 56-year-old woman, with unresectable NSCLC who initially received an adjuvant chemotherapy consisting of 4 cycles of cisplatin-pemetrexed. New lesions appeared and were classified pT3N0M0. Nivolumab therapy was then initiated. Figure 1 summarizes the key clinical and immunological data of the index case as well as the timeline of immune checkpoint analysis.Fig1Fig. 1

Timeline of clinical and biological analysis. Timeline reports the clinical signs of sarcoid-like reaction (upper part) and the biological parameters (lower part) of the index case. Boxed numbers, time of analysis by flow cytometry of PD-1 and PD-L1 expression by PBMC of the index case. WBC White blood cells; ACE Angiotensin converting enzyme

Immune checkpoint inhibitors have revolutionized the therapeutic landscape in oncology. However, several immune-related adverse events have been described, including damages in skin, gastrointestinal tract, kidney and nervous system. Among them, 11 cases of sarcoidoisis-like syndroms have been reported during melanoma treatment with ipilimumab, an anti-CTLA-4 mAb, used alone or in combination with nivolumab [1, 2]. More recently, studies reported that the inhibition of the PD-1 / PD-1 L axis may also induce such adverse effects. Sarcoid development has also been reported in 2 melanoma patients treated with nivolumab [3, 4] and in one melanoma patient treated with an anti-PD-L1 mAb [5]. SLR were also reported in 3 sarcoma [6] and one Hodgkin’s disease patient [7] treated with pembrolizumab. In lung cancer, one study reported a case of sarcoidosis with ipilumimab plus nivolumab [2]. A recent publication reported nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma [8]. We report here the first case of thoracic and cutaneous sarcoidosis in a patient with lung cancer and treated with nivolumab.

To overcome the side effects of ICI, immunosuppressive drugs, such as steroids, are usually used for a short period of time, with or without retracting ICI. Interestingly, in this case, SLR resolved in the absence of corticotherapy. In support, sarcoidosis spontaneously resolved in sarcoma patients treated with pembroluzimab [6].

It is interesting to note that the rapid decrease of PD-L1 expression precedes the resolution of SLR. One study has reported a local upregulation of PD-L1 expression in sarcoidosis and suggested that PD-1 blockade could constitute a therapeutic target in sarcoidosis [9]. The increase of PD-L1 may also result from the unlocking of cytokine production by activated T cells present in sarcoid lesions as well as in the peripheral blood [10]. Indeed, restoring the functions of hyper-activated TCR^high, and especially the secretion of IFN-γ, may favor sarcoidosis-like reaction [11].

Various lines of evidence support a role of the PD-1/PD-L1 pathway in the prevention and downregulation of SLR: (a) SLR can occur during anti-PD-1/PD-L1 and -CTLA-4 Ab therapies [1, 2], (b) we and others [6] have reported a favorable outcome after nivolumab discontinuation without corticosteroid, (c) we report that PD-L1 overexpression is concomitant with regression of clinical and radiological signs of SLR and (d) PD-L1^high B cells have been shown to reduce inflammation [12]. Collectively, our observations suggest that a dysregulated expression of PD-1 and PD-1 L is associated with clinical signs of sarcoidosis-like syndromes.

In conclusion, this study evidences an original case of sarcoidosis-like syndrome under nivolumab with spontaneous regression after treatment arrest, in the absence of corticotherapy. It also shows that, in a patient exhibiting autoimmune related effects, nivolumab arrest is associated with a delayed and complex modulation of PD-1 and PD-L1 expression on immune cells, which may contribute to restore immune homeostasis. This observation opens the question to which extent PD-1 expression in vivo controls PD-L1 expression.