Case Report: Sarcoid-Like Reactions and Tertiary Lymphoid Structures Following Dual Checkpoint Inhibition in a Patient with Early-Stage Lung Adenocarcinoma

Abstract

Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples. TP53 R181C, KRAS G12C and SMAD4 R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3+ regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures.

Blockade of PD-1 and LAG-3 expression on CD8+ T cells promotes the tumoricidal effects of CD8+ T cells

“…Zhao et al. observed up-regulated PD-1 expression in peripheral blood from patients with kidney cancer ( 38 ). Hence, LAG-3 and PD-1 may serve as biomarkers for assessing disease severity and predicting prognosis.…”

“…Indeed, coexpression of LAG-3 and PD-1 in peripheral blood T cells from patients with lung cancer are reported to be biomarkers for T cell dysfunction (37). Zhao et al observed up-regulated PD-1 expression in peripheral blood from patients with kidney cancer (38). Hence, LAG-3 and PD-1 may serve as biomarkers for assessing disease severity and predicting prognosis.…”

Splenic sarcoid reaction mimicking metastases in patients after uterine cancer surgery: a report of two cases

“…Several reports have documented the association between sarcoid reactions and various types of malignant tumors. The factors that cause malignancies to elicit sarcoid reactions are not clearly understood; however, many cases involve therapeutic agents, including immunosuppressive drugs [ 7 – 9 , 23 , 24 ]. Therefore, we summarized the reports of sarcoid reactions with a history of surgery over the past decade, including information regarding adjuvant drug use (Table 1 ).…”

“…Only one case of drug-induced sarcoid reaction could be diagnosed as sarcoid reaction by radiological findings after the drug was withheld [ 24 ]. Most sarcoid reactions are discovered at the time of primary tumor resection [ 5 , 6 , 8 , 9 , 13 , 16 , 18 , 20 – 22 , 26 , 27 , 29 , 30 ]; however, some (both drug-induced and non-drug-induced sarcoid reactions) are discovered 1 month to 5 years after surgery [ 10 , 14 , 15 , 17 , 19 , 23 , 25 , 28 , 31 ]. Granuloma formation is often found in lymph nodes, whereas spleen sarcoid reactions are more frequently found with non-drug-induced sarcoidosis.…”

“…Sarcoid or sarcoid-like reactions are histologic changes characterized by non-caseating epithelioid cell granulomas in patients without systemic sarcoidosis [ 1 , 2 ]. Sarcoid reactions have been associated with various tumors [ 1 , 3 , 4 ], including lymphoma, lung cancer [ 5 – 9 ], breast cancer [ 10 – 12 ], esophageal cancer [ 13 ], gastric cancer [ 14 ], colorectal cancer [ 15 – 19 ], biliary cancer [ 20 , 21 ], pancreatic cancer [ 22 ], melanoma [ 23 , 24 ], renal cell carcinoma [ 25 – 30 ], and bone cancer [ 31 ]. Sarcoidosis-like granulomas are predominantly found in the lymph nodes and stroma adjacent to tumors; however, involvement in the organs, such as the bone, skin, and spleen, is infrequent.…”