Lung Cancer Study Finds Molecular Features Affecting Immunotherapy Response

In Nature Genetics, investigators at the Broad institute, Dana-Farber Cancer Institute, and elsewhere consider features of non-small lung cancer (NSCLC) linked to checkpoint immunotherapy response. As part of a Stand Up to Cancer-Mark Foundation analysis, the team analyzed tumor exome and/or RNA sequence data in combination with clinical outcome profiles for 393 advanced NSCLC patients receiving anti-PD-1/PD-L1 checkpoint inhibitor treatment, highlighting several molecular features linked to better or worse progression-free survival and overall survival outcomes. Among other response-related features, their results suggest that TERT amplifications tend to coincide with poorer outcomes, for example, while alterations affecting the ATM gene; increased expression of immunoproteasome-related genes such as PSME1, PSME2, and PSMB9; or expression features resembling a dedifferentiated tumor subtype were linked to more favorable outcomes. "Comprehensive identification of predictors of checkpoint blockade response in patients with NSCLC has been limited by the availability of large, well-annotated patient cohorts with matched genomic data, particularly within individual cancer types," the authors explain, noting that findings from the current analysis suggest a "complex interplay between distinct signaling pathways (for example, CXCL9 versus TGF-beta signaling) and distinct cell types (for example, myeloid cells versus fibroblasts), shedding light on some of the multifaceted interactions underlying checkpoint blockade responsiveness."