HLA-E (Major Histocompatibility Complex, Class I, E)

ILC1 from NV-HCC also displayed enhanced IL-2/IL-15 signaling and interactions with CD8 + T cells via HLA-E, suggestive of potential antitumor crosstalk. While our single-cell cohort size was limited, necessitating validation in larger datasets, our study reveals etiology-associated differences in ILC phenotypes in HCC and provides insight into their potential roles in modulating immune responses within the tumor microenvironment.

In a human PBMC-engrafted NSG mouse xenograft lung cancer model, an anti-HER2 × anti-NKG2A BiNK markedly inhibited tumor growth as a monotherapy or in combination with pertuzumab. Cell depletion studies revealed that the BiNK enhanced antitumor activity of both NK and T cells. NKG2A blockade with potent and specific, fully human antibodies and BiNKs show promise for further development as cancer immunotherapeutics.

Co-editing the death receptor FAS increases the persistence of NKG2A-edited CAR NK cells both in vitro and in vivo. Together, our findings present a novel approach to enhance both cytotoxicity and persistence of CAR NK cell in cancer immunotherapy and reduce the risk of antigen-negative relapse.

Prior to submission, all novel alleles were confirmed with Oxford Nanopore sequencing. Linkage disequilibrium between HLA-F and its neighbouring loci HLA-A and HLA-E was also assessed.

First, the effectiveness of blocking the NKG2A-HLA-E interaction in vitro and in pre-clinical models as well as the presence of infiltrating NKG2A+ CD8+ T cells in some solid tumors has led to the generation of clinical grade NKG2A-specific monoclonal antibodies, pioneered by monalizumab, currently tested in clinical trials. Second, controlling NKG2A expression by genetic engineering constitutes a promising approach to improve advanced adoptive NK cell-based immunotherapies. Challenges include identifying predictive biomarkers of responsiveness, selecting appropriate clinical settings and optimizing combinatorial regimens.

Further, there was no significant association between sHLA-E levels and CRC outcome although enriched sHLA-E molecules were able to downregulated T cells mediated IFN-γ production in a dose-independent manner. Overall, these data suggest that in the Tunisian population, HLA-E*01:01/01:03 gene polymorphism and circulating sHLA-E molecules in female CRC patients may be important factors enabling gender-specific strategies for the diagnosis and treatment of this cancer.

Pre-treatment of blasts with an AHR inhibitor (AHRi) prior to NK cell killing assay downregulated key checkpoint molecules, including HLA-E, and key IFN-g signaling transcription factors (STAT1, IRF1) and led to enhanced NK cell killing among multiple FAB subsets in AML. The data support targeting the AHR pathway as a dual tumor intrinsic and immune targeting therapeutic strategy for AML, particularly in combination with NK cellular therapy.

Targeting loop molecules, such as PAST1, effectively potentiates tumor suppression by NK cells both in-vitro and in-vivo. Thus, our study uncovered a heretofore unrecognized nonautonomous mechanism for PSAT1, as well as a molecular buff for YBX1, to drive tumor growth by evading NK immunity, providing a promising target for NK cytotherapy of immune cold tumors.

Our study demonstrates the first successful expansion of adaptive NK cells with robust functional responses from donors with chronic viral infection. This approach creates opportunities for NK cell-based therapies alone or in combination with monoclonal antibodies contributing to HBV functional cure strategies and the treatment of HBV-driven cancers.

CD70 is a promising target for NK cell-based immunotherapy in AML. However, IFN-γ-dependent upregulation of HLA molecules on AML cells contributes to resistance to ADCC. These findings underscore the need for rationale combination strategies in clinical trials to overcome this inducible immune escape mechanism.

These findings suggest that NK cells may play an important role in the tumor immune microenvironment of choriocarcinoma through HLA-E expression.

Our study examined two "first-in-class" RNA Pol I inhibitors, CX-5461 and BMH-21, which differentially regulate NK cell-activating and inhibitory ligand expression in MM. This effect was modulated by Lenalidomide and Panobinostat. Moreover, RNA Pol I inhibition enhanced Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC) of NK cells against MM, uncovering novel immuno-mediated antitumor mechanisms.