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Celebrating the 10th Anniversary

A decade of discoveries in Cancer Discovery. For the community. By the Community.


Uncovering Genetic Underpinnings of Immune Checkpoint Blockade Resistance

image for Ribas, et al. article

Arguably the most important clinical advance in oncology of the past decade has been the development of immune checkpoint inhibitors that release constraints on T- cell activation to promote antitumor immune responses. Immune checkpoint blockade with inhibitors of the PD-1/PD-L1 axis can lead to long-lasting responses in a subset of patients, but predicting which patients will respond remains challenging, in part due to significant heterogeneity in downstream signaling patterns and therapeutic responses among tumors despite shared driver mutations. In 2015, Skoulidis, Heymach, and colleagues performed an integrative analysis of transcriptional, mutational, copy-number, and proteomic data from KRAS-mutant non–small cell lung cancers (NSCLC) and found that these tumors could be classified into three subsets with distinct co-occurring mutations, underlying biology, and potential therapeutic vulnerabilities, one of which was a subgroup with co-occurring STK11 (also known as LKB1) mutations. These tumors were not only distinguished by inactivation of LKB1– AMPK signaling and adaptation to oxidative stress but also by a lack of immune system engagement relative to the other subtypes. A subsequent 2018 study by Skoulidis, Goldberg, Greenawalt, Geese, Albacker, Heymach, and colleagues showed that immune checkpoint blockade with PD-1 inhibitors was significantly less effective in the subgroup of patients with KRAS-mutant NSCLC with co-occurring STK11/LKB1 mutations than the other subgroups, and supportive data in a syngeneic mouse model of Kras-mutant lung adenocarcinoma showed that loss of Stk11/Lkb1 confers resistance to PD-1 blockade. In addition to co-occurring KRAS and STK11/LKB1 mutations, loss-of-function mutations in JAK1 and JAK2 also were found to be associated with primary resistance to PD-1 blockade in patients with melanoma or colorectal cancer with a high mutational load, as shown by Shin, Ribas, and colleagues in 2017. Accompanying work in patient-derived cell lines showed that inactivating JAK1/2 mutations abrogated signaling through the IFNγ receptor pathway, which resulted in insensitivity to the IFNγ-produced in response to PD-1 blockade and inability to activate IFNγ-dependent PD-L1 expression. Collectively, these studies provided some of the earliest evidence for genetic mechanisms of primary resistance to immune checkpoint blockade and have guided subsequent efforts to stratify patients for immunotherapy.

Read 2015 article by Skoulidis and colleagues

Read 2018 article by Skoulidis and colleagues

Read 2017 article by Shin and colleagues


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