Cytokines, Chemokines, and Other Biomarkers of Response for Checkpoint Inhibitor Therapy in Skin Cancer

Abstract

Immunotherapy for skin malignancies has ushered in a new era for cancer treatments by demonstrating unprecedented durable responses in the setting of metastatic Melanoma. Consequently, checkpoint inhibitors are now the first-line treatment of metastatic melanoma and widely used as adjuvant therapy for stage III disease. With the observation that higher tumor mutational burden correlates with a better response, checkpoint inhibitors are tested in other skin cancer types of known high tumor mutational burden with promising results and recently became the first-ever FDA-approved treatment for metastatic Merkel cell carcinoma. The emerging new standards-of-care will necessitate more precise biomarkers and predictors for treatment response and immune-related adverse events. Measurable immune-related mediators are currently under investigation as factors that promote or block the response to cancer immunotherapy and may provide insights into the underlying immune response to the tumor. Cytokines and chemokines are such mediators and are crucial for facilitating the recruitment and activation of specific subsets of leukocytes within the microenvironment of skin cancers. The exact mechanisms of how these meditators, both immunological and non-immunological, operate in the tumor microenvironment is an area of active research, so to reliable biomarkers of responses to cancer immunotherapy. Here, we will review and summarize the expanding body of literature for immune-related biomarkers pertaining to Melanoma, Basal cell carcinoma, Squamous cell carcinoma, and Merkel cell carcinoma, highlighting clinically relevant checkpoint inhibitor therapy biomarker advancements.

Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

“…Cytokines and chemokines play essential roles in a number of important biological processes (Ahmed et al, 2014;Chen et al, 2018;Doring et al, 2014;Edderkaoui, 2017;Janssens et al, 2018;Ridiandries et al, 2018;Sokol and Luster, 2015;Turner et al, 2014), including hematopoiesis (Wright et al, 2002;Youn et al, 2000) and cancer metastasis (Agarwal et al, 2019;Amedei et al, 2013;Bridge et al, 2018;Chow and Luster, 2014;King et al, 2017;Marcuzzi et al, 2018;Nagarsheth et al, 2017). Because of its clearly demonstrated essential roles for hematopoiesis, CXCL12 is one of the most intensely studied CXC subfamily chemokine factor in the bone marrow (BM) niche (Abe-Suzuki et al, 2014;Aurrand-Lions and Mancini, 2018;Broxmeyer and Kim, 1999;Lewellis and Knaut, 2012;Sugiyama et al, 2006).…”

Remember to assess the ‘whole’ patient: a further immune‐related adverse event of programmed cell death 1 checkpoint inhibition

“…Immune checkpoint inhibition (ICI) is now a mainstay in the fight against multiple forms of cancer. In dermatology they are a first‐line option in the treatment of malignant melanoma and show promise in the treatment of other skin malignancies including squamous and Merkel cell carcinomas . However, as their utilization increases so does our understanding of their immune‐related adverse events (irAEs).…”

What's the point in checking the skin?

“…In recent years immune checkpoint inhibitors (ICIs) have become an important weapon in the oncologist's armamentarium in their fight against multiple forms of cancer. In dermatology they are a first‐line option in the treatment of metastatic melanoma and show significant potential in the treatment of advanced‐stage squamous and Merkel cell carcinomas . However, their ever‐burgeoning use comes at a cost, with increasing reports of immune‐related adverse effects (irAEs) including cutaneous toxicities (commonly lichenoid eruptions, eczema and vitiligo) .…”

“…In dermatology they are a first‐line option in the treatment of metastatic melanoma and show significant potential in the treatment of advanced‐stage squamous and Merkel cell carcinomas . However, their ever‐burgeoning use comes at a cost, with increasing reports of immune‐related adverse effects (irAEs) including cutaneous toxicities (commonly lichenoid eruptions, eczema and vitiligo) . Programmed cell death receptor‐1 (PD‐1) is an immune checkpoint receptor expressed on the cell surface of activated lymphocytes which, when stimulated by its ligand programmed death‐ligand 1 (PD‐L1), inhibits T‐cell activation (particularly CD8 + T cells).…”

“…Programmed cell death receptor‐1 (PD‐1) is an immune checkpoint receptor expressed on the cell surface of activated lymphocytes which, when stimulated by its ligand programmed death‐ligand 1 (PD‐L1), inhibits T‐cell activation (particularly CD8 + T cells). In the steady state this is important for immune tolerance but has less salubrious functions when exploited by PD‐L1‐expressing tumour cells to evade recognition …”