Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade

By Pei-Ling Chen, Whijae Roh, A. Reuben, Z. Cooper, C. Spencer, P. Prieto, John P Miller, R. Bassett, V. Gopalakrishnan, K. Wani and 34 more. Cancer Discovery, 2016

871 citations recorded by the source corpus.

Immune checkpoint blockade represents a major breakthrough in cancer therapy, however responses are not universal. Genomic and immune features in pre-treatment 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 metastatic melanoma patients initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 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 these studies, 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 CTLA-4 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.

Subfields: Immunology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2975afcf0998c516d8daa2a10d30bfd88f0439a7

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In Pulmonary and Respiratory Medicine

Lisa M. Coussens

Citations in the corpus

Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “(Chen et al., 2016), the list of genes that changed under treatment from their Supplementary Table 10.”
Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients (2017, background): “CD8 T-cell expansion and migration results in higher number of tumor-specific CD8 T cells at the tumor site, consistent with observations reporting an increase in CD8 T-cell infiltration in early on-treatment tumor biopsies from melanoma patients that achieve clinical responses to PD-1–targeted ther”
Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “PD-L1 expression, tumor mutational burden, tumor infiltrating lymphocytes (TILs) or related gene expression signatures have been explored as potential predictors and various other markers are currently under investigation (Chen et al., 2016; Cristescu et al., 2018; Garon et al., 2015; Hugo et al., 2”
Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, positive): “Recent studies suggest that the degree of T cell infiltration— which might be regulated by tumor cell-intrinsic signaling pathways and gene regulatory networks—is a critical factor (Chen et al., 2016; Ji et al., 2012; Kortlever et al., 2017; Peng et al., 2015; Spranger et al., 2015;Wang et al., 2016”
T Cell Dysfunction in Cancer (2018, background): “…of melanoma patients under CTLA-4 and PD-1 blockade observed that, while response to PD-1 blockade was associated with increased expression of genes related to cytotoxicity, antigen processing, and IFNg signaling, therapy resistance correlated with increased VEGFA expression (Chen et al., 2016).”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “In addition, preliminary evidence in serial tumour biopsies of PD-1 antibody-treated melanoma patients suggests that induction of PD-L1 expression on tumour cells early in the course of therapy improves response prediction (Chen et al, 2016).”
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab (2017, background): “Further, the location of CD8+ T cells at the invasivemargin of tumors may indicate an effective immune response (Chen et al., 2016; Spranger et al., C B snoit atu mlanol cf o noitca rF A Pe r c en ts ur vi va l P e rc e n ts u r vi va l Ipi Naive OS Years 0 0 50 100 1 2 3 p = 0.048 Mutation…”
Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy (2017, neutral): “Therefore, the combination therapy should increase the intratumoral infiltration by CD8+ T cells, which may attract enough T cells with tumor specificity to reverse the primary resistance to PD-1 blockade therapy (Chen et al., 2016; Ribas, 2015).”
Defining T cell states associated with response to checkpoint immunotherapy in melanoma (2018, neutral): “, 2014) or during early treatment (Chen et al., 2016).”