Abstract
Simple SummaryDespite the successes of immune checkpoint therapy in treating metastatic skin cancers, most patients either fail to respond or become unresponsive to immunotherapy. We found that the cell–cell communication of two different immune cell types, macrophages and memory B cells, correlate very strongly with the response to immunotherapy. We built a mathematical model based on these results that predict different skin cancers would have different response rates and predict that a high ratio of memory B cells to macrophages is optimal for a response to immunotherapy.The advent of immune checkpoint therapy for metastatic skin cancer has greatly improved patient survival. However, most skin cancer patients are refractory to checkpoint therapy, and furthermore, the intra-immune cell signaling driving response to checkpoint therapy remains uncharacterized. When comparing the immune transcriptome in the tumor microenvironment of melanoma and basal cell carcinoma (BCC), we found that the presence of memory B cells and macrophages negatively correlate in both cancers when stratifying patients by their response, with memory B cells more present in responders. Moreover, inhibitory immune signaling mostly decreases in melanoma responders and increases in BCC responders. We further explored the relationships between macrophages, B cells and response to checkpoint therapy by developing a stochastic differential equation model which qualitatively agrees with the data analysis. Our model predicts BCC to be more refractory to checkpoint therapy than melanoma and predicts the best qualitative ratio of memory B cells and macrophages for successful treatment.
Highlights
Checkpoint immunotherapy can drive durable responses in many metastatic cancers, with most adverse events being grades 1 or 2 [1,2,3,4]
Current FDA-approved checkpoint inhibitors fall into two categories: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors
We found that anti-inflammatory gene expression correlates well with the percentage of macrophages found in post-treatment non-responders, indicating that macrophages in the melanoma tumor microenvironment (TME) are involved in the refractory response to immunotherapy (Figure 3E)
Summary
Checkpoint immunotherapy can drive durable responses in many metastatic cancers, with most adverse events being grades 1 or 2 [1,2,3,4]. Current FDA-approved checkpoint inhibitors fall into two categories: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors. CTLA-4 expressed by T regulatory cells (Tregs) outcompete costimulatory molecules on cytotoxic T lymphocytes (CTLs) necessary for their. Cancers 2020, 12, 2946 activation, which results in anergy and eventual apoptosis. Cancer and immune cells express PD-L1, which binds to PD-1 expressed by effector cells including CTLs and by innate immune cells such as natural killer (NK) cells [5]. Binding of PD-1 on effector cells inhibits their cytotoxicity and promotes anergy and eventual apoptosis [1]. Checkpoint therapy’s utility remains limited, with most patients either not responding or acquiring resistance to treatment [3]
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