NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer.

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.

Functional characterization of the MyD88 homologs in Strongylocentrotus purpuratus.

Toll-like receptor signaling is an evolutionarily conserved pathway to induce the expression of immune mediators in response to encounters with pathogens. MyD88 is a central adapter connecting the intracellular domain of the receptors to downstream kinases. Here, we conducted a comprehensive assessment of the MyD88 family in an echinoderm, Strongylocentrotus purpuratus. Of five SpMyD88s only two closely related proteins, SpMyD88A and SpMyD88B, are functional in mammalian cell lines as their overexpression facilitates the activation of the downstream transcription factor NF-κB. This requires the presence of the endogenous mammalian MyD88s, and domain swapping indicated that the death domains of S. purpuratus MyD88 are unable to efficiently connect to the respective domains of the vertebrate IRAK kinases. This suggests that the interaction surfaces between the signaling mediators in this conserved signaling pathway are not as conserved as previously thought but were likely shaped and evolved by pathogenic selection over evolutionary timescales.

Visible-blind photodetector based on p-i-n junction GaN nanowire ensembles.

We report the synthesis, fabrication and extensive characterization of a visible-blind photodetector based on p-i-n junction GaN nanowire ensembles. The nanowires were grown by plasma-assisted molecular beam epitaxy on an n-doped Si(111) substrate, encapsulated into a spin-on-glass and processed using dry etching and metallization techniques. The detector presents a high peak responsivity of 0.47 A W(-1) at - 1 V. The spectral response of the detector is restricted to the UV range with a UV-to-visible rejection ratio of 2 x 10(2). The dependence on the incident power and the operation speed of the photodetector are discussed.