Review: PD‐L1 as an emerging target in the treatment and prevention of keratinocytic skin cancer

Abstract

Recent advances in the understanding and targeting of immune checkpoints have led to great progress in immune therapies against many forms of cancer. While many types of immune checkpoints are currently targeted in the clinic, this review will focus on recent research implicating the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis as an emerging focus for the treatment of keratinocytic tumors. PD-L1 is of particular interest in nonmelanoma skin cancer (NMSC), as it is not only upregulated in these tumors but is stimulated by environmental ultraviolet exposure. This response may also make PD-L1 an excellent target for photochemoprevention using topically applied small molecule inhibitors.Here, we summarize recent investigations on PD-L1 expression and clinically relevant immune checkpoint inhibitor treatment in cutaneous squamous cell carcinoma, basal cell carcinoma, and head and neck squamous cell carcinoma, as well as small molecule agents targeting PD-L1 that may be useful for clinical development aiming at treatment or prevention of NMSC.

Inhibition of UV-Induced Stress Signaling and Inflammatory Responses in SKH-1 Mouse Skin by Topical Small-Molecule PD-L1 Blockade

“…Immunotherapeutics have played a critical role in advancing the treatment of many malignancies, including high-risk skin cancers. The PD-1/PD-L1 immune checkpoint has been investigated in much detail, and recent literature has shown that cSCC is among the many tumor types to overexpress PD-L1 ( Dickinson et al, 2021 ; Vaishampayan et al, 2023 ; Zerdes et al, 2018 ). In contrast, given the keratinocytic origin of cSCC, the responsiveness of epidermal PD-1/PD-L1 expression to carcinogenic environmental stressors (including solar UV light) remains poorly explored, and the effects of PD-1/PD-L1 modulation on skin photodamage are equally unknown.…”

“…Expression of PD-1 is typically restricted to immune cells (including T cells, B cells, and NK cells), and immunotherapies using systemic mAbs against PD-1 have been approved for many advanced malignancies, including cSCC, basal cell carcinoma, and melanoma ( Blum et al, 2018 ; Constantinidou et al, 2019 ; Vaishampayan et al, 2023 ). In contrast, PD-L1 is either basally expressed or inducible in most cells of the body.…”

“…Overexpression of PD-L1 in cSCC is common, and recent literature has shown a correlation between increased PD-L1 expression and advanced clinical risk assessment in these tumors ( Dickinson et al, 2021 ; Schaper et al, 2017 ; Slater and Googe, 2016 ; Stravodimou et al, 2021 ). In addition to PD-1–directed interventions, blockade of PD-L1 by immunotherapeutics is now used clinically in many types of cancer (including melanoma and basal cell carcinoma) and is being studied for use as adjuvant therapy for treatment of cSCC ( Lin et al, 2021 ; Vaishampayan et al, 2023 ).…”

Enhancing Skin Cancer Immunotheranostics and Precision Medicine through Functionalized Nanomodulators and Nanosensors: Recent Development and Prospects

“…Immunotherapy for skin cancers has shown higher success rates than other cancers. Therapy using anti-PD-1 (anti-programmed-death 1) for melanomas, BCC, CSCC, and Kaposi’s sarcoma has shown a 40% response rate [ 54 , 55 ]. Cytokine therapy using Type-1 interferon and interleukin has been tested, but high toxicity and low response rates limited its use in mainstream therapeutics [ 56 , 57 , 58 ].…”

Nanomaterials for Skin Cancer Photoimmunotherapy

“…The immune system plays a critical role in recognizing, eliminating, and controlling tumor progression. However, cancer cells develop mechanisms to avoid it, namely: (i) downmodulation of components of antigen processing and presentation machinery; (ii) an environment that promotes suppressor immune cells, such as regulatory T cells (Treg), an immunosuppressive subset of CD4+ T-cell family, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages, which are anti-inflammatory macrophages (M2-like); (iii) production of soluble factors associated with immunosuppression, such as TGF-β and IL-10; (iv) and upregulation of ligands for coinhibitory receptors that downmodulate programmed death ligand-1 (PD-L1) [24][25][26][27][28][29].…”