The evolution of the tumor immune microenvironment in immunosuppressed patients with cutaneous squamous cell carcinoma

Abstract Immunosuppression is a major risk and prognostic factor for cutaneous squamous cell carcinoma (cSCC). Immune checkpoint inhibition is approved for the treatment of cSCC, yet most immunosuppressed patients are ineligible for immunotherapy. Better understanding on the tumor microenvironment of cSCC in the context of immunosuppression (i.e., organ transplant recipients, patients with hematological malignancies or autoimmune diseases or acquired immunodeficiencies such as HIV) is of utmost importance for proper implementation of immunotherapy as a therapeutic alternative for these patients. In this study, we characterized the immune cell phenotype of cSCC from immunocompetent (IC) and immunosuppressed (IS) patients treated at two Cancer Centers. We also compared the immune phenotype changes through the steps of skin carcinogenesis between IC and IS patients, and among individuals with distinct causes for immunosuppression. To evaluate the TME dynamics during tumorigenesis, we analyzed specimen of normal epithelium, keratinocytic intraepidermal neoplasia (including carcinoma in situ and actinic keratosis), or invasive cSCC. The analysis of cSCC tumor microenvironment was performed by multiplex immunofluorescence (Opal 12-Color), CyTOF and single-cell RNA sequencing. Our analysis revealed that densities of CD68+ and effector T-cells are diminished in IS patients compared with IC. An analysis of precursor lesions revealed that the density of tumoral CD8+LAG3+ T-cells in patients with hematological malignancies was significantly lower than in patients with other types of immunosuppression. Compared with patients with other types of immunosuppression, patients with hematological malignancies had a higher density of stromal CD4+ T cells in precursor lesions but a lower density of CD20+ B cells. Overall, IS patients had worse outcomes than IC patients, and the densities of CD68+ and CD8+LAG3+ cells were prognostic in this cohort. CD8+LAG3+ was significantly associated with DSS of IS patients indicating the impact of dysfunctional cytotoxic T cells on these patients’ survival. Our findings provide a detailed insight into the underlying immune alterations from tumor inception through growth and invasion, in patients with different types of immunosuppression. This dataset will serve as a benchmark data to guide clinical trials aiming to treat this patient population and provide a potential rationale for designing safer immunotherapy clinical trials for the population of IS patients with cSCC or other head and neck cancers. Citation Format: Mica D. E. Glaun, Frederico O. Gleber-Netto, Priyadharsini Nagarajan, Tongxin Xie, Shamima Akhter, Yu Han Chen, Erez Baruch N. Baruch, Michael K. Wong, Emily Y. Chu, Kenneth Y. Tsai, Elsa R. Flores, Deborah A. Silverman, Ryan P. Goepfert, Murat Cobanoglu, Jared Burks, Padmanee Sharma, James P. Allison, Jeffrey N. Myers, Neil D. Gross, Moran Amit. The evolution of the tumor immune microenvironment in immunosuppressed patients with cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-074.