Association of <i>ALOX12B</i> gene alterations with TMB and immune checkpoint inhibitor (ICI) outcomes.

Abstract

e14546 Background: ALOX12B encodes 12R-lipoxygenase (12R-LOX), an arachidonic-acidlipoxygenase that generates fatty-acid hydroperoxides and downstream lipid signalingintermediates. Arachidonic-acid–derived lipid mediators can shape antitumor immunity bymodulating myeloid and T-cell programs within the tumor microenvironment. As a result LOX-pathway perturbations may influence ICIsensitivity. Despite this rationale, the relevance of ALOX12B to antitumor immunity and ICIoutcomes has not been systematically defined. We therefore tested whether ALOX12Balterations identify a subgroup with enhanced clinical benefit from ICI therapy. Methods: In cBioPortal’s “TMB and Immunotherapy (MSK, Nat Genet 2019)” cohort, tumorswere grouped as ALOX12B-altered (n = 24; mutations/structural variants) or unaltered(n = 1,637). Non-synonymous tumor mutation burden (mut/Mb) was compared betweengroups. Overall survival (OS) from ICI initiation was assessed by Kaplan–Meier and log-rank ,subtypes including melanoma and colorectal cancer (CRC) subsets. Co-alterations weresummarized. TIMER3 Mutation and Immunotherapy_outcome modules were used fororthogonal immune-infiltration and independent ICI outcome support. Results: ALOX12B alterations occurred in 24/1,661, enriched in melanoma (12/24) and CRC(4/24). Altered tumors had markedly higher TMB (median 43.37 vs 5.87 mut/Mb; p = 1.72×10^-9).Overall survival (OS, months) favored ALOX12B-altered tumors across cancers (median58.0 vs 18.0 months; p = 0.036), in melanoma ( 58.0 vs 42.0 months; p = 0.204), and in CRC(median not reached vs 15.0 months; p = 0.0309). Most Frequent co-alterations includedTERT (67%) and EPAS1 (60%). TIMER3 Mutation-module analysis linked ALOX12B mutation to higher T-cell–relatedinfiltration signatures—particularly CD8+ and cytotoxic/exhausted T-cell programs—acrossmultiple deconvolution methods, including ImmuCellAI, xCell, ABIS, CIBERSORT-ABS,quanTIseq, and the TIMER algorithm (nominal p&amp;lt;0.05).In the TIMER3Immunotherapy_outcome module, higher ALOX12B expression was associated with bettersurvival after ICI treatment in glioblastoma patients (GBM_PRJNA482620; Cox coefficient =−2.11, p = 0.035). Conclusions: ALOX12B alterations define a rare, hypermutated subgroup with improved survivalfollowing immune checkpoint inhibition. Across complementary analyses, ALOX12B-altered tumors demonstrate a strong TMB signal and supportive immune-contexture features, includingCD8/Treg-related infiltration indicators, together suggesting that ALOX12B status may serve asa robust biomarker of ICI benefit. These findings warrant deeper mechanistic study andvalidation in larger, tumor-specific immunotherapy datasets with multivariable modeling toconfirm independent predictive value and establish clinical applicability.