@article {1051121, title = {Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade}, journal = {Cancer Discov}, volume = {6}, number = {8}, year = {2016}, month = {2016 Aug}, pages = {827-37}, abstract = {UNLABELLED: 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. Cancer Discov; 6(8); 827-37. {\textcopyright}2016 AACR.See related commentary by Teng et al., p. 818This article is highlighted in the In This Issue feature, p. 803.}, issn = {2159-8290}, doi = {10.1158/2159-8290.CD-15-1545}, author = {Chen, Pei-Ling and Roh, Whijae and Reuben, Alexandre and Cooper, Zachary A and Spencer, Christine N and Prieto, Peter A and Miller, John P and Bassett, Roland L and Gopalakrishnan, Vancheswaran and Wani, Khalida and De Macedo, Mariana Petaccia and Austin-Breneman, Jacob L and Jiang, Hong and Chang, Qing 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 Haydu, Lauren and Lazar, Alexander J and Patel, Sapna P and Hwu, Patrick and Hwu, Wen-Jen and Diab, Adi 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 Prieto, Victor and Davis, R Eric and Ma, Wencai and Overwijk, Willem W and Sharpe, Arlene H and Hu, Jianhua and Futreal, P Andrew and Blando, Jorge and Sharma, Padmanee and Allison, James P and Chin, Lynda and Wargo, Jennifer A} }