Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified.



These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827-37. ©2016 AACR.See related commentary by Teng et al., p. 818This article is highlighted in the In This Issue feature, p. 803.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Pei-Ling
PL
Chen
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Whijae
W
Roh
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Alexandre
A
Reuben
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zachary A
ZA
Cooper
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Christine N
CN
Spencer
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Peter A
PA
Prieto
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
John P
JP
Miller
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Roland L
RL
Bassett
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Vancheswaran
V
Gopalakrishnan
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Khalida
K
Wani
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mariana Petaccia
MP
De Macedo
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jacob L
JL
Austin-Breneman
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hong
H
Jiang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Qing
Q
Chang
Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sangeetha M
SM
Reddy
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wei-Shen
WS
Chen
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Michael T
MT
Tetzlaff
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Russell J
RJ
Broaddus
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Michael A
MA
Davies
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jeffrey E
JE
Gershenwald
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Lauren
L
Haydu
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Alexander J
AJ
Lazar
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sapna P
SP
Patel
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Patrick
P
Hwu
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wen-Jen
WJ
Hwu
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Adi
A
Diab
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Isabella C
IC
Glitza
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Scott E
SE
Woodman
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Luis M
LM
Vence
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ignacio I
II
Wistuba
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Rodabe N
RN
Amaria
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Lawrence N
LN
Kwong
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Victor
V
Prieto
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
R Eric
RE
Davis
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wencai
W
Ma
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Willem W
WW
Overwijk
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
Arlene H
AH
Sharpe
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jianhua
J
Hu
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
P Andrew
PA
Futreal
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jorge
J
Blando
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Padmanee
P
Sharma
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
James P
JP
Allison
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Lynda
L
Chin
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. JWargo@mdanderson.org.
Jennifer A
JA
Wargo
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D015415:Biomarkers; D001706:Biopsy; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D056747:Immunomodulation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D015415:Biomarkers; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor