Mechanistic Assessment and Treatment of Immune Related Adverse Events

Immune related adverse events (irAEs) secondary to immune checkpoint blockade (ICB) or other immunotherapies are a significant problem for Veterans and the general public given the increasing use of ICB and other immunomodulatory agents. It is therefore of critical importance to improve understanding and optimize treatment regimens for irAEs. Dermatologic toxicity is among the most frequent irAE and thus understanding dermatologic irAEs is an immediately accessible window into the autoimmune pathology caused by ICB. Lessons from skin irAEs thus can inform approaches to other irAEs. Our objective is to define the role and function of resident memory T cells in skin irAEs due to anti-PD-1 monotherapy (pembrolizumab or nivolumab). As ICBs and immunomodulation are increasingly used in other contexts, irAEs are inevitable and increasing in incidence. Completion of the work here will further our goal to define the pathophysiologic mechanisms of immunomodulator-induced adverse events and develop a precision medicine approach to ultimately facilitate rational novel therapeutic strategies to improve efficacy and tolerability while preventing or rapidly mitigating irAEs. Our central hypothesis is that CD8+ resident memory T cells are critical drivers of skin irAEs. These hypotheses build both on our prior work to define molecular signatures of morphologically similar non-irAE skin rashes, culminating in development of the rmAD43 and rmPV45 signatures, our analyses of public datasets on ICB-induced irAEs, and our preliminary work on analyzing ICB-induced skin irAEs. We will test this hypothesis using complementary approaches including innovative deep analysis of prospectively collected patient samples and recapitulation and modulation of phenotypes using relevant mouse models. The work we propose here will also develop an understanding of skin irAEs that will offer insights to determine pathways involved in immune related adverse events in other organs and help identify predictive markers of these toxicities. Our team of experts in immunology, immunotherapy, melanoma, skin biology, and bioinformatics will test this central hypothesis and achieve our objective via the following specific aims: 1) Determine significance and profile of CD8+ Trm cells in human skin irAE and 2) Define activity of IL-17A and its modulation in skin irAE using relevant murine models. We will leverage our prior work in both single cell RNA sequencing and the DNFB mouse dermatitis and NINJA mouse models in a highly innovative and integrative manner to determine both signatures and mechanisms of cutaneous irAEs as well as identify and test rational therapeutic targets to mitigate these side effects. The expected outcome is to provide insight into the mechanisms underlying skin irAE secondary to ICB and a deeper understanding of associated pathways associated with skin-directed irAEs. We will also test strategies to treat skin irAEs which can be rapidly translated for clinical utility. These results will allow us to further develop evidence-based strategies for skin irAEs and will form the foundational basis for future clinical trials to test hypotheses and improve therapeutic strategies for all irAEs and ultimately benefit Veterans health. Project Number: 1I01CX002750-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Rajan Kulkarni | Institution: PORTLAND VA MEDICAL CENTER, PORTLAND, OR | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 IMMA-G (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11053214