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Background CD274 locus (9p24.1), which harbors PD-L1, is frequently co-amplified with PD-L2. However, the clinical and immunotherapeutic implications of these co-alterations remain poorly defined.Methods Patients with tumors harboring CD274 amplified tumors (≥3 copies) were identified from MSKCC IMPACT cohort (n=95,182). Co-amplification of PD-L2 and JAK2 located in the 9p24.1 locus were also evaluated. We assessed the prognosis impact of these co-amplifications on overall survival (OS) and OS after initiation of immune checkpoint blockade (ICB).Results Among 95,182 patients in the MSKCC cohort, PD-L1 amplification was detected in 370 cases (0.4%) with a mean number of copies of 4.0 ± 0.9 (range 3-6 copies). Co-amplification of PD-L2 and JAK2 occurred in 91.2% and 75.5% of cases, respectively. Amplified tumors exhibited significantly higher aneuploidy and tumor mutational burden. Higher prevalence of PD-L1 amplification and co-amplifications were observed in HPV-associated cancers (anal, vaginal, penile, cervical, head and neck) with an overall prevalence per cancer type ranging from 0.8 to 4.9%, small cell lung cancer (1.8%), bladder (0.7%), sarcoma (0.5%), and breast cancers (0.4%).Tumors with any amplification in the 9p24.1 locus had significantly shorter overall survival when compared to patients without amplification (p<10-12) regardless of tumor origin. When comparing OS based on the occurrence of co-amplifications, no significant difference was observed for PD-L1 amplified, PD-L1/PD-L2 or PD-L1/PD-L2/JAK2 co-amplification for median OS ( 21.4, 21.5 and 21.8 months, respectively).In patients receiving ICB (N=108), the median follow up was 36 months and further OS analyses were time-restricted at 3-years.Median OS from start of ICB was 21.6 months in patients with PD-L1 and PD-L2 co-amplification versus 14.7 months for patients with PD-L1 amplification alone (p=0.07). No significant difference was observed for patients harboring PD-L1/PDL2/JAK2 co-amplification compared to patients with PD-L1/PD-L2 co-amplification.In the patients, receiving anti PD-1, patients with PD-L1/PD-L2 co-amplification had higher OS compared to patients with isolated PD-L1 amplification (20.4 vs 12.1 months, p=0.05).Conclusions PD-L1 amplification is rare but recurrent across diverse tumor types, particularly HPV-associated cancers, and often co-occurs with PD-L2 and JAK2 co-amplification. Co-amplification seems to associate with improved outcomes following anti-PD-1-based therapy, potentially due to dual PD-L1/PD-L2 blockade.Ethics Approval IRB was approved for this study.