Scientists now know how melanoma skin cancer evolves to resist immunotherapy

Good news! Cancer is history (soon)!

"... The team found that relapsing melanoma tumors often acquire genomic DNA copy-number variants, which delete or amplify sections of DNA. These variants frequently affect genes that control cancer cells’ ability to self-destruct in response to damage caused by immune attacks. The cumulative effect of copy-number changes, often involving multiple cell-death genes, allows cancer cells to survive immune attacks, leading to tumors relapsing or regrowing months or years after the initial therapy-induced tumor shrinkage. ..."

From the highlights and abstract:

"Highlights

• Acquired-resistant melanomas amplify anti-apoptotic and/or delete pro-apoptotic genes

• Models of acquired ICI resistance recapitulate apoptotic evasion due to CNVs

• Preexisting and de novo resistance-driver CNVs occur commonly or privately in subclones

• Lowering the apoptotic threshold salvages ICI sensitivity and prevents relapse

Summary

Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse.

Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. 

Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively.

By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. 

AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs.

In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses.

Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution."

Scientists now know how melanoma skin cancer evolves to resist immunotherapy | UCLA "Following the discovery, researchers have identified a strategy to possibly prevent treatment relapses"

Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors (open access)

Graphical abstract: