ABSTRACT
Background
The KIR receptors present on the natural killer (NK) cells play a crucial role by exercising cytotoxicity to eliminate tumor cells. Both KIR and class-I HLA molecules exhibit extensive polymorphism. Although RB1 inactivation triggers the initiation of retinoblastoma; however additional immune alterations trigger tumor development. The aim was to explore the KIR/HLA polymorphism and its role in the pathogenesis of retinoblastoma.
Methods
Patients with unilateral, non-familial retinoblastoma were enrolled as cases. Healthy individuals matched for ethnicity were enrolled as controls. KIR genotyping was performed by sequence-specific primer assay. The investigated KIR genes included: inhibitory (2DL1, 2DL2, 2DL3, 2DL4, 2DL5A, 2DL5B), activating (2DS1, 2DS2, 2DS3, 2DS4*FUL, 2DS4*DEL, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) and pseudogenes (2DP1, 3DP1*FUL, 3DP1*DEL). In addition, HLA ligands were investigated by sequence-specific oligonucleotide assay for HLA-A, B, and C locus.
Results
KIR genotyping was performed in 48 cases and 107 controls. The mean age of cases was 2.9 ± 2.2 years (range: 0.25–10). Among the 19 KIR genes, the frequency of KIR2DS4*FUL (p = 0.0019) and 2DS5 (p = 0.0095) was increased among cases. HLA ligands were investigated in 25 cases and 50 controls. The frequency of HLA ligands (C1/C2, Bw4, A3/A11) was similar among cases and controls. However, the KIR/HLA combination frequency for KIR3DS1/HLA-Bw4 was decreased in cases (p = 0.006).
Conclusion
It is the pioneer study to report the association of killer cell immunoglobulin-like receptors in retinoblastoma. KIR2DS4*FUL and KIR2DS5 had a susceptible, and KIR3DS1/HLA-BW4 had a protective role in retinoblastoma. The results will aid in exploring the therapeutic potential of NK cell-based therapy for retinoblastoma.
Acknowledgments
The research associate fellowship of Dr. Madhulika Sharma and Dr. Navdeep Mangat from Indian Council of Medical Research, New Delhi is duly acknowledged. We are grateful to Director, PGIMER for the research fellowship of Ms. Tanvi Bhatia. We would like to acknowledge the staff members of the Transplantation Laboratory, Manchester Royal Infirmary, Manchester, United Kingdom for their technical support with HLA typing.
Disclosure statement
No potential conflict of interest was reported by the authors.
Statement of author contribution
RA: study design, supervising experimental work, manuscript writing; MS: Experimental work, analysis of data, assistance in manuscript writing; US: contribution of patient samples, editing and approval of manuscript; KP: supervising experimental work, editing and approval of manuscript and logistic support; TB & NKM: experimental work; NK: editing and approval of manuscript; DB: contribution of samples, editing and approval of manuscript, logistic support.
Data availability statement
The data that support the findings of this study are available from the corresponding author,[RA], upon reasonable request.