AUTHOR=Zhang Wenjing , Kong Yujia , Li Yuting , Shi Fuyan , Lyu Juncheng , Sheng Chao , Wang Suzhen , Wang Qinghua 

TITLE=Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.798474

DOI=10.3389/fimmu.2021.798474

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Immune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.</p></sec><sec><title>Methods</title><p>We comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.</p></sec><sec><title>Results</title><p>We identified 27 SMGs, including four novel SMGs (<italic>COL3A1</italic>, <italic>NRAS</italic>, <italic>NARS2</italic>, and <italic>DCC</italic>) that are associated with ICI efficacy and well-known driver genes. <italic>COL3A1</italic> mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45–0.91, <italic>p</italic> = 0.012), whereas immune resistance was observed in patients with <italic>NRAS</italic> mutations (HR: 1.42, 95% CI: 1.10–1.82, <italic>p</italic> = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11–1.82, <italic>p</italic> = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR &lt; 1, <italic>p</italic> &lt; 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23–0.87, <italic>p</italic> = 0.017).</p></sec><sec><title>Conclusion</title><p>We uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.</p></sec>