Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma

Abstract

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.

Identification of clinical relevant biomarkers to predict response to immune checkpoint blockade (ICB) in melanoma remains challenging. Here, the authors show that stroma remodelling and reduced cell division are associated with durable response to anti-PD1 in a mouse model of melanoma and in ICB-treated patients.