Background/Purpose: Salivary glands (SGs) can be damaged by immune checkpoint inhibitor (ICI) therapy. In patients with ICI-induced SG dysfunction, 60% progress to fulfill the ACR-EULAR 2016 classification criteria for primary Sjögren’s syndrome (pSS), owing to immune foci in SGs and/or anti-SSA autoantibody positivity. We report the SG tissue analysis of 2 patients with SG dysfunction after treatment with anti PD-L1 and PD-1 ICIs, compared to that of a dry mouth (“sicca”) control and pSS patient.

Methods: Immunostaining for CD4, CD8, Keratin7 (K7), AQP5, Ki67, and PD-L1 was performed in two parotid SG biopsies from patients following ICI therapy, and in control and a pSS patient tissue. The first patient (male, 52 yrs) received fortnightly infusions of 10mg/kg durvalumab (anti-PD-L1 therapy), for non-small cell carcinoma (NSNLC). After 43 weeks (22 cycles) of treatment, the patient was not capable of producing stimulated or unstimulated whole saliva, and demonstrated SSA-positivity. The second patient (female, 74) received infusions of pembrolizumab (anti-PD-1) every 3 weeks for treatment of NSNLC, at a flat dose of 200mg. This patient was not capable of producing unstimulated whole saliva, and demonstrated reduced 0.12mL/min stimulated whole saliva production, after 15 weeks (5 cycles) of treatment. Both patients were SSA-positive following ICI treatment.

Results: In contrast to control and pSS tissue, following anti-PD-L1 and anti-PD-1 blockade, only few AQP5⁺, classically shaped acinar cell clusters were observed in the parotid SG after treatment with anti-PD-L1 and anti-PD-1 biologicals (Fig. 1a-c). The parenchyma was dominated by hybrid epithelial structures containing a mixture of AQP5⁺ (acinar cell marker) and K7⁺ (intercalated duct marker) cells (Figure 1d-f). AQP5⁺K7⁺ cells were also detected. Cells with this unusual phenotype are not seen in control/pSS tissue. More Ki67⁺ proliferating ID-like cells were detected following PD-L1 or PD-1 therapy, compared to control and pSS SGs. The SG post-PD-L1 and PD-1 therapy demonstrated focal and disperse lymphocytic sialadentitis. Infiltration was CD4⁺ T cell-rich, although CD8⁺ T cells were also present. CD4⁺ and CD8⁺ T cells were observed in-between and inside hybrid structures. CD20⁺ B-cells were infrequent. No germinal centers, lymphoepithelial lesions or antibody class-switching following ICI therapy were observed. PD-L1 expression was detected in the SG parenchyma following anti-PD-L1 therapy. 

Conclusion: Conventional SG acinar cells were lacking following both anti-PD-L1 and PD-1 ICI therapy. SGs demonstrated presence of hybrid intercalated duct-like structures. Understanding which mechanisms and dynamics underpin this aberrant parenchyma may be crucial to understand how SG dysfunction post-ICI therapy, and potentially other affected organs. Furthermore, although patients post-ICI therapy may fulfill the ACR-EULAR 2016 pSS criteria and demonstrate focal lymphocytic sialadentitis, the further histopathological characteristics do not resemble pSS.

Figure 1 a-c) H&E staining of the parotid salivary gland in sicca control, pSS and post-PD-L1 ICI therapy, showing lack of conventional acinar cell morphology following ICI treatment. d-f) AQP5 and Keratin 7 (K7) double immunostaining, showing presence of unusual hybrid mixed AQP5+K7+ cells post-PD-L1 therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lack-of-conventional-acinar-cells-in-the-salivary-gland-following-anti-pd-l1-and-anti-pd-1-immune-checkpoint-inhibitor-therapy/