Anti-PD-1 Therapy Does Not Influence Hearing Ability in the Most Sensitive Frequency Range, but Mitigates Outer Hair Cell Loss in the Basal Cochlear Region

Abstract

The administration of immune checkpoint inhibitors (ICIs) often leads to immune-related adverse events. However, their effect on auditory function is largely unexplored. Thorough preclinical studies have not been published yet, only sporadic cases and pharmacovigilance reports suggest their significance. Here we investigated the effect of anti-PD-1 antibody treatment (4 weeks, intraperitoneally, 200 μg/mouse, 3 times/week) on hearing function and cochlear morphology in C57BL/6J mice. ICI treatment did not influence the hearing thresholds in click or tone burst stimuli at 4–32 kHz frequencies measured by auditory brainstem response. The number and morphology of spiral ganglion neurons were unaltered in all cochlear turns. The apical-middle turns (<32 kHz) showed preservation of the inner and outer hair cells (OHCs), whilst ICI treatment mitigated the age-related loss of OHCs in the basal turn (>32 kHz). The number of Iba1-positive macrophages has also increased moderately in this high frequency region. We conclude that a 4-week long ICI treatment does not affect functional and morphological integrity of the inner ear in the most relevant hearing range (4–32 kHz; apical-middle turns), but a noticeable preservation of OHCs and an increase in macrophage activity appeared in the >32 kHz basal part of the cochlea.

Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice

“…ABR tests were performed to follow up changes in auditory function by measuring hearing thresholds as previously described [ 9 , 51 ]. In brief, mice were anesthetized with a mixture of ketamine-xylazine injection (100 mg/kg and 10 mg/kg, intraperitoneally, respectively).…”

“…Underlying factors of cochlear aging include genetic susceptibility, otological disorders, and environmental factors, for example, increased noise exposure [ 5 , 6 ]. The main pathological processes presumed to play a crucial role in the development of ARHL are ischemia, excitotoxicity [ 6 ], increased level of reactive oxygen species (ROS) [ 7 ], apoptosis [ 8 ], and low-grade inflammation [ 9 , 10 ]. As a result, age-related degeneration of stria vascularis, auditory hair cells (HCs), and spiral ganglion neurons (SGNs) could be primarily observed [ 6 , 11 , 12 ].…”

Ototoxicity Review: A Growing Number of Non–Platinum‐Based Chemo‐ and Immunotherapies

“…As such, it is plausible that the mechanism through which these checkpoint inhibitors cause inner ear damage is through disruption of the melanocytic cells within the inner ear, similar to the rare autoimmune disorder Vogt‐Koyanagi‐Harada syndrome 11 . Other work has suggested that the outer hair cells may be affected at the basal turn of the cochlea in animal models 12 …”

“…11 Other work has suggested that the outer hair cells may be affected at the basal turn of the cochlea in animal models. 12 The next point worth noting regarding these nonplatinum-based ototoxic agents is that the majority of these studies were published within the last 15 years (after 2005). Interestingly, many of the agents and classes of drugs over this recent history include chemo-and immunotherapeutics agents.…”