Cancer immunotherapies are preferred over conventional treatments which are highly cytotoxic to normal cells. Focus has been on T cells but natural killer (NK) cells have equal potential. Concepts in cancer control and influence of sex require further investigation to improve successful mobilization of immune cells in cancer patients. Acute lymphoblastic leukemia (ALL) is a hematological malignancy mainly of B cell (B-ALL) and T cell (T-ALL) subtypes. Influence of ALL on NK cell is still unclear. Targeted next-generation sequencing was conducted on 62 activating/inhibitory receptors, ligands, effector, and exhaustion molecules on T-ALL (6 males) and normal controls (NC) (4 males and 4 females). Quantitative PCR (q-PCR) further investigated copy number variation (CNV), methylation index (MI), and mRNA expression of significant genes in T-ALL (14 males), NC (12 males and 12 females), and B-ALL samples ( N = 12 males and 12 females). Bioinformatics revealed unique variants particularly rs2253849 (T>C) in KLRC1 and rs1141715 (A>G) in KLRC2 only among T-ALL (allele frequency 0.8-1.0). Gene amplification was highest in female B-ALL compared to male B-ALL (KLRC2, KLRC4, and NCR3, p < 0.05 ) and lowest in male T-ALL cumulating in deletion of KLRD1 and CD69. MI was higher in male ALL of both subtypes compared to normal (KIR2DL1-2 and 4 and KIR2DS2 and 4, p < 0.05 ) as well as to female B-ALL (KIR3DL2 and KIR2DS2, p < 0.05 ). mRNA expressions were low. Thus, ALL subtypes potentially regulated NK cell suppression by different mechanisms which should be considered in future immunotherapies for ALL.

Introduction: Sex shapes immune response with possible consequence on tumor immune escape. Acute lymphoblastic leukemia (ALL) predominates in males while ovarian cancer (OC) occurs in females. NK cells essential for tumor killing may have male preponderance. Association of sex, NK cell activity and malignancies is unclear. We hypothesize that sex differentially affects KIR expressions in sex-biased cancers. Method: Expression of inhibitory (KIR2DL1-5 and KIR3DL1-3) and activating (KIR2DS1-2 and 4-5 and KIR3DS1) genes in B-, T-cell ALL, OC and normal controls were determined by reverse-transcription polymerase-chain-reaction. Result: All normal males (but not females) expressed the framework genes and generally maintained haplotype A, except KIR3DL1. Normal females expressed more activating KIRs. Frequencies of KIR2DL1, 2DL4 and 2DS2 were significantly reduced among ovarian cancer patients. Sex difference in frequencies of KIR expression was not detected in ALL as majority were undetectable except framework gene KIR3DL2, was more frequent among T-ALL. Conclusion: Cancers may be associated with reduced KIR expression and influence of sex requires investigation.