Table 1

Clinical implications of tumor HLA-I expression

Cancer typePatient noPreoperative treatmentLoss of HLAConclusionHLA analysis methodReference
90No40% (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 approach20
198No27.2% (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.WES205
And NSCLC (cohort 1)
Various cancers (cohort2)
369 (cohort 1)
1166 (cohort 2)
Anti-PD-1/PDL-1 or anti-CTLA-4 or combination23.5% (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
NSCLC68No30% (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
Melanoma181No43%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 WGS218
PDAC243No35%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
HNSCC158No20% (total loss)HLA-I loss associated poor survival was observed only in PD-L1 +ve group.IHC (EMR8-5 clone)219
ESCC90No61.1%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
ESCC70No43%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
91No54%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 sequencing220
(MSI-high and MSS)
(161; MSI-h
139; MSS)
No70% (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
293NoTumor 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)
395Chemotherapy65.3% (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 carcinoma80No45%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
1190No48.3%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-)
732Chemotherapy and endocrine treatment34% (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 cancer136 (SCC; 103, AC; 33)No94% (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.