Divergent Resistance Mechanisms to Immunotherapy Explain Responses in Different Skin Cancers

SIMPLE SUMMARY: Despite 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. ABSTRACT: 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.