Human Endogenous Retrovirus-H Long Terminal Repeat- Associating Protein 2 (HHLA2) is a Novel Immune Checkpoint Protein in Lung Cancer which Predicts Survival

Abstract

Background: Lung cancer is one of the most frequently diagnosed malignancies. Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a recently discovered ligand of the B7 family. Blocking this immune checkpoint has become an important treatment option for lung cancer. Methods: The study includes 62 biopsy specimens either bronchoscopic or CT-guided biopsies diagnosed as lung cancer in Hospitals of Faculty of Medicine, Mansoura University, Egypt during the period from 2016 to 2020. Immunohistochemical Staining for HHLA2 and EGFR was performed. HHLA2 expression was assessed in different pathological types of lung Cancer, and it was correlated with other clinicopathologic parameters and patient prognosis. Results: We found a significant association between HHLA2 expression and metastasis. About 83% of patients presented with metastasis showed positive expression of HHLA2 compared to 44.4% in patients with no metastasis (p=0.02). Also, results show significant mild positive correlation between expression of HHLA2 and EGFR markers (p=0.045). The mean OS time in cases with positive HHLA2 expression was nearly half that of patients with negative expression of the markers. However, this difference was not statistically significant. But, PFS of patients was significantly lower among the group with positive expression of HHLA2 compared to the group with negative expression of HHLA2 (p= 0.01). Conclusions: This study reports that recently discovered, HHLA2 is over expressed in lung cancer associating with higher stage. It is also correlated with EGFR overexpression. HHLA2 could serve as a predictor of progression and distant metastasis. Also, it has potential to be effective immune target in lung cancer immunotherapy such as checkpoint blockade and antibody-drug conjugate treatment.

HERVs and Cancer—A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

“…While both proteins are part of oncogenic signaling pathways, HHLA2 has been detected in several human cancers [ 195 ]. HHLA2 was found to be overexpressed in basal breast cancer [ 357 ], triple-negative breast cancer [ 357 ], colorectal cancer [ 358 ], lung cancer [ 359 , 360 , 361 ], liver cancer [ 362 ], bladder urothelial carcinoma [ 363 ], ccRCC [ 364 , 365 , 366 ], pancreatic cancer [ 367 , 368 , 369 ], osteosarcoma [ 370 ], oral squamous cell carcinoma [ 371 ], and many other cancers [ 357 , 364 ] compared to adjacent normal tissue or healthy controls. Additionally, elevated HHLA2 protein levels were associated with tumor size, tumor stage, lymph node metastasis, and low relapse-free and overall survival in these cancers [ 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 , 369 , 370 , 371 ].…”

“…HHLA2 was found to be overexpressed in basal breast cancer [ 357 ], triple-negative breast cancer [ 357 ], colorectal cancer [ 358 ], lung cancer [ 359 , 360 , 361 ], liver cancer [ 362 ], bladder urothelial carcinoma [ 363 ], ccRCC [ 364 , 365 , 366 ], pancreatic cancer [ 367 , 368 , 369 ], osteosarcoma [ 370 ], oral squamous cell carcinoma [ 371 ], and many other cancers [ 357 , 364 ] compared to adjacent normal tissue or healthy controls. Additionally, elevated HHLA2 protein levels were associated with tumor size, tumor stage, lymph node metastasis, and low relapse-free and overall survival in these cancers [ 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 , 369 , 370 , 371 ]. Thus, HHLA2 might not only become a suitable prognostic marker, as shown by Zhang et al (2021) in a Chinese cohort [ 372 ], but also a potential immunotherapy target for patients who do not respond to other immune checkpoint inhibitors, such as PD-1 inhibitors.…”

KIR3DL3-HHLA2 and TMIGD2-HHLA2 pathways: The dual role of HHLA2 in immune responses and its potential therapeutic approach for cancer immunotherapy

“…EGFR Epidermal growth factor receptor (EGFR) is a growth factor receptor involved in cell differentiation and proliferation [35] . B7 family members are affected by EGFR tyrosine kinase inhibitor resistance in gastric cancer [30] , and HHLA2 expression is higher in the EGFR mutant group in lung cancer [36] , [37] , [38] . There is a negative correlation between EGFR and HHLA2 expression in cell lines and non-small-cell lung carcinoma [39] .…”

Human endogenous retrovirus-H long terminal repeat-associating 2: The next immune checkpoint for antitumour therapy

“…Overexpressed in multiple human cancer types, the prognostic role of HHLA2 remains controversial ( Table 1 ). Several studies indicated that overexpression of HHLA2 in tumour cells was associated with unfavorable clinical outcomes and shorter survival rate in patients with prostate cancer, 26 neuroendocrine tumours, 27 hepatocellular carcinoma, 28 , 29 , 30 lung adenocarcinoma, 31 , 32 , 33 , 34 gastric cancer, 35 oral squamous cell carcinoma, 36 bladder urothelial carcinoma, 37 intrahepatic cholangiocarcinoma, 38 colorectal carcinoma, 39 , 40 osteosarcoma, 41 and triple negative breast cancer. 17 On the contrary, HHLA2 was a protective factor predicting low mortality rate in patients with pancreatic cancer, 14 , 42 , 43 epithelial ovarian cancer, 44 malignant glioma, 45 and recurrent or unresectable advanced gastric cancer.…”