Genetic Aberrations in the CDK4 Pathway Are Associated with Innate Resistance to PD-1 Blockade in Chinese Patients with Non-Cutaneous Melanoma

Abstract

Purpose: PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti-PD-1 therapy remains unclear.Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n ¼ 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti-PD-1 antibody. Copy-number variations (CNVs) for the genes CDK4, CCND1, and CDKN2A were assayed using a TaqMan copy-number assay in a validation cohort (n ¼ 85). The effect of CDK4/6 inhibitors combined with anti-PD-1 antibody monotherapy was evaluated in PD-1-humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models.Results: WES revealed several significant gene copynumber gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti-PD-1 therapy was validated in 85 patients with melanoma (P < 0.05). RNA-Seq analysis of CDK4-normal cell lines and CDK4-normal tumors showed altered transcriptional output in TNFa signaling via NF-kB, inflammatory response, and IFNg response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy (P < 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model.Conclusions: In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti-PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti-PD-1 antibody for the treatment of advanced melanomas.

Acral lentiginous melanoma: Basic facts, biological characteristics and research perspectives of an understudied disease

“…The effect on tumour growth correlated with decreased phosphorylation of RB Transcriptional Corepressor 1 (Rb1) (Kong et al., 2017). Complementary to these findings, Yu et al (2019) showed that, in humanized mouse and PDX models, palbociclib improved response to immune checkpoint blockade. Although this was not observed specifically in acral melanoma models, supporting evidence suggests that these results may be applied to this melanoma subtype.…”

“…Oncogenic activation of the CDK4 pathway through copy-number gains in CDK4, CCND1 and loss of CDKN2A is a common genetic feature of acral melanomas (Bastian et al, 2000;Curtin et al, 2005;Furney et al, 2012;Kong et al, 2017;Liang et al, 2017 (Kong et al, 2017). Complementary to these findings, Yu et al (2019) showed that, in humanized mouse and PDX models, palbociclib improved response to immune checkpoint blockade. Although this was not observed specifically in acral melanoma models, supporting evidence suggests that these results may be applied to this melanoma subtype.…”

The Diverse Function of PD-1/PD-L Pathway Beyond Cancer

“…Additionally, Chen et al (181) found that tumor cells expressing CD38, which regulates the adenosine production pathway, escape from checkpoint inhibitor-mediated immune attack. In patients with advanced melanoma, resistance to PD-1 blockade therapy was reported to be linked to genetic aberrations in the cyclin D–cyclin-dependent kinase 4 (CDK4) pathway (182). Moreover, anti-PD-1 antibody binding to Fc receptors expressed on tumor-associated macrophages can partially be removed from tumors, which may reduce the effect of PD-1 antibodies (183).…”

CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors

“…Three out of five patients presented with CCND1 amplification ( 5 ). A retrospective study of melanoma also showed that 30 out of 56 patients with innate resistance to anti-PD-1 therapy presented with CCND1 amplification ( 6 ). Although there are currently few reported cases, the clinical phenomena suggest the potential value of CCND1 amplification as a biomarker for predicting negative therapeutic effects of ICIs.…”