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. 2016 Nov;48(11):1327-1329.
doi: 10.1038/ng.3677. Epub 2016 Sep 26.

Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy

Nadeem Riaz  1   2   3 , Jonathan J Havel  1 , Sviatoslav M Kendall  1 , Vladimir Makarov  1 , Logan A Walsh  1 , Alexis Desrichard  1 , Nils Weinhold  2 , Timothy A Chan  1   2   3
Affiliations

Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy

Nadeem Riaz et al. Nat Genet. 2016 Nov.

Abstract

Immune checkpoint blockade has shown significant promise as an anticancer treatment, yet the determinants of response are not completely understood. Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma (n = 174). Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity. Our findings have implications for the personalization of immunotherapy.

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Figures

Figure 1
Figure 1. Somatic mutations of SERPINB3 and SERPINB4 predict improved survival from treatment with anti-CTLA4 therapy
(a) Overall survival of patients with SERPINB3 mutations in cohort 1 (n=64, p=0.005) and cohort 2 (n=110, p=0.05). (b) Overall survival of patients with either SERPINB3 or SERPINB4 mutations in cohort 1 (p=0.01) and cohort 2 (p=0.005) (c) Survival by SERPINB3/4 mutations in the TCGA melanoma cohort. All statistical tests are log-rank. (n=262; p=NS) (d) Proportion of patients with SERPINB3 or SERPINB4 mutations with clinical benefit or response in cohort 1 (p=0.04) and cohort 2 (p=0.001) (Fisher’s exact test; error bars correspond to standard error). (e) Mutation load as a function of SERPINB3 or SERPINB4 mutations in cohort 1 (p=0.002) and cohort 2 (p=0.003) (Wilcox rank-sum test).
Figure 2
Figure 2. Characteristics of mutations in SERPINB3 and SERPINB4
(a) Oncoprints of SERPINB3 and SERPINB4 mutations in the two cohorts. (b) Diagrams showing location of mutations in SERPINB3 and SERPINB4 (data from both cohorts combined). Blue bar represents putative reactive center loop (RCL) domain. (c) Location of mutations on 3-dimensional protein structure of SERPINB3. Red: mutated amino acid; blue represents putative RCL domain. (d) Location of mutations on 3-dimensional protein structure of SERPINB4
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