Divergent resistance mechanisms to immunotherapy explains response in different skin cancers.

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 differential intra-immune signaling between cancers driving the 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 when stratifying patients by response, with memory B cells more present in responders. Inhibitory immune signaling is reduced in melanoma responders and is increased 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. We show differences in tumor progression and regression that could serve as a diagnostic and predict the optimal ratio of macrophages and memory B cells for successful treatment.