Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors.
Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzed PD-L1, PD-L2, PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database. We found that in some tumor types, PD-L2 expression is more closely linked to Th1/IFNG expression and PD-1 and CD8 signaling than PD-L1 In contrast, mutational load was not correlated with a Th1/IFNG gene signature in any tumor type. PD-L1, PD-L2, PD-1, CYT expression, and mutational density are all positive prognostic features in melanoma, and conditional inference modeling revealed PD-1/CYT expression (i.e., an inflamed tumor microenvironment) as the most impactful feature, followed by mutational density. This study elucidates the highly interdependent nature of these parameters, and also indicates that future biomarkers for anti-PD-1/PD-L1 will benefit from tumor-type-specific, integrated, mRNA, protein, and genomic approaches.
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.|Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russia, 119333.|The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Ludmila
0000-0003-2813-3094
L
Danilova
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Hao
H
Wang
Department of Dermatology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Joel
J
Sunshine
Department of Dermatology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Genevieve J
GJ
Kaunitz
Department of Pathology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Tricia R
TR
Cottrell
Department of Dermatology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Haiying
H
Xu
Department of Dermatology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Jessica
J
Esandrio
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.|The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.|Department of Pathology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Robert A
RA
Anders
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.|The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Leslie
L
Cope
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.|The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Drew M
DM
Pardoll
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.|The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.|The Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Charles G
CG
Drake
Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287; jtaube1@jhmi.edu.|The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.|Department of Dermatology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.|Department of Pathology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Janis M
JM
Taube
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D004252:DNA Mutational Analysis; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009154:Mutation; D059645:Mutation Rate; D011379:Prognosis; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism; D016016:Proportional Hazards Models; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor
PD-1; PD-L1; PD-L2; melanoma; mutational load