@article{67b3418018c44901903cb7bf7f683b69,
title = "Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade",
abstract = "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. SIGNIFICANCE: 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.",
author = "Chen, {Pei Ling} and Whijae Roh and Alexandre Reuben and Cooper, {Zachary A.} and Spencer, {Christine N.} and Prieto, {Peter A.} and Miller, {John P.} and Bassett, {Roland L.} and Vancheswaran Gopalakrishnan and Khalida Wani and {De Macedo}, {Mariana Petaccia} and Austin-Breneman, {Jacob L.} and Hong Jiang and Qing Chang and Reddy, {Sangeetha M.} and Chen, {Wei Shen} and Tetzlaff, {Michael T.} and Broaddus, {Russell J.} and Davies, {Michael A.} and Gershenwald, {Jeffrey E.} and Lauren Haydu and Lazar, {Alexander J.} and Patel, {Sapna P.} and Patrick Hwu and Hwu, {Wen Jen} and Adi Diab and Glitza, {Isabella C.} and Woodman, {Scott E.} and Vence, {Luis M.} and Wistuba, {Ignacio I.} and Amaria, {Rodabe N.} and Kwong, {Lawrence N.} and Victor Prieto and {Eric Davis}, R. and Wencai Ma and Overwijk, {Willem W.} and Sharpe, {Arlene H.} and Jianhua Hu and {Andrew Futreal}, P. and Jorge Blando and Padmanee Sharma and Allison, {James P.} and Lynda Chin and Wargo, {Jennifer A.}",
note = "Funding Information: J.A. Wargo acknowledges the Melanoma Research Alliance Team Science Award, the Kenedy Memorial Foundation grant #0727030, Melanoma Research Alliance Team Science Award, the Kenedy Memorial FoundationU54CA163125, a STARS award, UT Regents, and the generous philanthropic support of several families whose lives have been affected by melanoma. This work was supported by NIHNational Institutes of Health grants 1K08CA160692-01A1(J.A. Wargo), U54CA163125(Z.A. Cooper, J.A. Wargo, and L. Chin), T32CA009599 (P.A. Prieto), T32CA163185 (P.-L. Chen and W.-S. Chen), and 2P30CA016672 (I.I. Wistuba). W. Roh is supported by the CPRIT Graduate Scholar Award. I.C. Glitza holds a Conquer Cancer Foundation ASCO Young Investigator Award. L. Chin is a CPRIT Scholar in Cancer Research and was supported by a grant from the Cancer Prevention Research Institute of Texas (R1204). P.A. Futreal holds CPRITCancer Prevention and Research Institute of Texas funding (R1205 01), a Robert Welch Distinguished University Chair (G-0040), and a STARS award. R.N. Amaria has received research support from Merck, Novartis/Array, and Bristol-Myers Squibb. W.-J. Hwu has received research support from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and MedImmune. I.I. Wistuba has received support from MD Anderson{\textquoteright}s Institutional Tissue Bank. This work was supported by MD Anderson{\textquoteright}s Institutional Tissue Bank Award (2P30CA016672)from the National Cancer Institute. This study was also supported by philanthropic contributions to The University of Texas MD Anderson Cancer Center Melanoma Moon Shot Program. Publisher Copyright: {\textcopyright} 2016 American Association for Cancer Research.",
year = "2016",
month = aug,
doi = "10.1158/2159-8290.CD-15-1545",
language = "English (US)",
volume = "6",
pages = "827--837",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "8",
}