Clinical implications of tumor HLA-I expression
| Cancer type | Patient no | Preoperative treatment | Loss of HLA | Conclusion | HLA analysis method | Reference |
| NSCLC (early) | 90 | No | 40% (LOH) | LOH at HLA was found to occur as late event in cancer evolution as an immune evasion mechanism. HLA LOH harboring cancer cells had enrichment of neoantigens predicted to bind lost HLA alleles. | WES with computational approach | 20 |
| NSCLC (advanced) | 198 | No | 27.2% (LOH) | Patients received ICIs after tumor sampling and therapy response rate was between 31%–36%. TMB, PD-L1 expression or LOH at HLA alone was not predictive marker for ICI response. Combination of HLA-LOH and TMB, provided a better prediction of ICIs responsiveness. | WES | 205 |
| Melanoma And NSCLC (cohort 1) Various cancers (cohort2) | 369 (cohort 1) 1166 (cohort 2) | Anti-PD-1/PDL-1 or anti-CTLA-4 or combination | 23.5% (Cohort 1) 22.9% (Cohort 2) | LOH (in at least in one locus) was associated with poor survival. HLA heterozygosity together with high TMB showed the best survival rate. Melanoma patients with HLA-B44 haplotype had better survival, while HLA-B15:01 haplotype was associated with poor survival. | WES and targeted-sequencing (MSK-IMPACT) | 204 |
| NSCLC | 68 | No | 30% (total loss) | Expression levels PD-L1 or HLA-I alone was not a prognostic factor. The density of TILs dependent on HLA-I status but not PD-L1. | IHC (W6/32 clone) | 217 |
| Melanoma | 181 | No | 43% | Loss of HLA was associated with progressive disease in patients who received anti-CTLA4 before anti-PD1, indicating critical effect of anti-PD1 in early course of therapy. | IHC (EMR8-5 clone), RNA-seq and WGS | 218 |
| PDAC | 243 | No | 35% | High classical HLA-I expression was associated with shorter survival. High HLA-G (35.7%) and HLA-E (36.7%) expression were detected and correlated with shorter overall survival. | IHC (HLA-ABC; EMR8-5 clone, HLA-E; MEM-E/02 clone, HLA-G; 4H84 clone) | 207 |
| HNSCC | 158 | No | 20% (total loss) | HLA-I loss associated poor survival was observed only in PD-L1 +ve group. | IHC (EMR8-5 clone) | 219 |
| ESCC | 90 | No | 61.1% | High expression of HLA-I and PD-L1 were correlated with poor overall survival. HLA-I expression status alone was not a significant prognostic factor. | IHC (EMR8-5 clone) | 212 |
| ESCC | 70 | No | 43% | 90% of patients with lymph node metastasis had loss of HLA. Even if the central tumor exhibited strong HLA-I expression, majority of lymph node metastases had HLA-I downregulation. Weak HLA-I expression was associated with shorter overall survival. | IHC (EMR8-5 clone) | 211 |
| Colorectal (MSI-high) | 91 | No | 54% | MSI-high colorectal cancer had higher mutation frequency in HLA-I related genes compared with the non-MSI counterparts. 72% of patients had mutations in at least one HLA-I related gene, including transactivator NLRC5. NLRC5 mutation harboring tumors had lower HLA-I expression. | IHC (HLA-A; HCA-2 ab, HLA-BC; HC10 ab), sanger sequencing | 220 |
| Colorectal (MSI-high and MSS) | 300 (161; MSI-h 139; MSS) | No | 70% (MSI-high) 39% (MSS) | High HLA expression correlated with high TIL density. In MSS tumors, reduced HLA-I was associated with higher pathological node stage and higher disease stage. Reduced HLA expression in MSS group was significantly associated with lower overall survival and disease-free survival. There was no correlation with overall survival in MSI-high group. | IHC (EMR8-5 clone) | 221 |
| Gastric cancer (MSI-high) | 293 | No | Tumor center: 45% (total loss), 25% (locus loss) Invasive margin: 37.5% (total loss), 22.9% (locus loss) | Loss of HLA was correlated with low TIL density only in PD-L1+ group. HLA-I expression itself was not a prognostic factor. However, high TIL density was a good prognostic factor only in HLA-I+ and PD-L1+ group. | IHC (EMR8-5 clone and locus specific antibodies) | 209 |
| Gastric cancer (MSS and MSI-low) | 395 | Chemotherapy | 65.3% (total loss either in invasive margin or tumor center) | Loss of HLA-I was associated with negative β2M expression. HLA-I negative tumors showed aggressive pathologic conditions, had lower TIL density and caused worse survival rate. | IHC (EMR8-5 clone and locus specific antibodies) | 210 |
| Hepatocellular carcinoma | 80 | No | 45% | High HLA-I expression was correlated with better recurrence free survival. PD-L1 low and HLA-I high expression improved overall survival. | IHC (EMR8-5 clone) | 222 |
| Breast cancer (HER2+) | 1190 | No | 48.3% | High HLA-A, -B and -C expression was associated with high TIL density. All three HLAs were negatively correlated with ER, PR and AR expression. All HLA-I high and high TIL showed the best overall survival. Down regulation of HLA in nodal metastases compared with primary site was observed. | IHC (Locus specific antibodies) | 223 |
| Breast cancer (HR+, HER2-) | 732 | Chemotherapy and endocrine treatment | 34% (low expression) 9% (total loss) | High HLA expression was associated with better response to chemotherapy and elevated TIL density. No correlation between better survival and HLA-I expression was detected. | IHC (EMR8-5 clone) | 224 |
| Cervical cancer | 136 (SCC; 103, AC; 33) | No | 94% (SCC) 87% (AC) | High HLA-E (33%–37%) and HLA-G (28%–31%) was detected in primary tumors. HLA-E expression was lower in metastatic site, while HLA-G expression was higher. Larger tumors had lower classical HLA expression. Low classical HLA expression and high unclassical expression had poorer survival. | IHC (HLA-A; HCA-2 ab, HLA-BC; HC10 ab, HLA-E; MEM-E/02 clone, HLA-G; 4H84 clone) | 225 |
AC, adenocarcinoma; AR, androgen receptor; ER, estrogen receptor; ESSC, esophageal squamous cell carcinoma; HLA, human leucocyte antigen; HNSCC, head and neck squamous cell carcinoma; HR, Hormone receptor; ICI, immune checkpoint inhibitors; IHC, immunohistochemistry; LOH, loss of heterozygosity; MSI, microsatellite instable; MSS, microsatellite stabile; NLRC5, NOD-like receptor caspase protein 5; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; PR, progesterone receptor; SCC, Squamous cell carcinoma; TIL, tumor infiltrating lymphocyte; WES, whole exome sequencing.