High expression of CIITA, the master MHC-II regulator, as a predictor of survival benefit from immune checkpoint inhibitors across solid tumors.

e14589 Background: The class II major histocompatibility complex transactivator (CIITA) is the master regulator of MHC class II expression and a potential determinant of tumor immunogenicity. However, its prevalence, immunologic correlates, and association with immune checkpoint inhibitor (ICI) outcomes in solid tumors remain incompletely defined. We characterized CIITA expression patterns, immune features, and clinical outcomes in a large real-world pan-cancer cohort. Methods: We analyzed 514 patients with advanced solid tumors profiled by RNA sequencing performed in a clinical laboratory (OmniSeq INSIGHT, Buffalo, NY). CIITA-high tumors were defined as those in the ≥75th percentile (n = 107). Associations between CIITA-high status and immune biomarkers were evaluated using univariable and multivariable logistic regression. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan–Meier methods and Cox proportional hazards models in the full cohort, in ICI-treated patients, and in patients who never received ICIs. Results: High CIITA expression was observed in 20.8% of patients. Ovarian cancer demonstrated the strongest enrichment (35% in CIITA-high vs 20% in CIITA-low), with a multivariable odds ratio (OR) of 3.31 (95% CI, 1.02–10.8; p = 0.047). High CIITA expression was strongly associated with increased expression of multiple immune checkpoint molecules (PD-1, PD-L1, PD-L2, CTLA4, LAG3, TIM3, BTLA) and HLA class II molecules (ORs 4–30) (all p < 0.01, univariate). Several MHC II–related HLA genes, including HLA-DOA, HLA-DOB, HLA-DMA, HLA-DMB, and HLA-DQB2, remained independently associated with CIITA-high status in multivariable analyses. Among 217 patients treated with ICIs, CIITA-high was associated with markedly improved OS (median 3.64 vs 1.18 years; multivariable p = 0.02). No survival difference was observed in 272 patients who never received ICIs (median 3.91 vs 3.50 years; p = 0.30). Conclusions: CIITA-high tumors represent a distinct immune-active subgroup characterized by widespread upregulation of checkpoint and antigen-presentation pathways. CIITA-high status correlates significantly and independently with substantial survival benefit in patients receiving ICIs, but not in those treated without ICIs. CIITA may serve as an emerging, biologically grounded biomarker for predicting ICI responsiveness across solid tumors.