Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.
We prove a stability version of a general result that bounds the permanent of a matrix in terms of its operator norm. More specifically, suppose $A$ is an $n \times n$ matrix over $\mathbb{C}$ (resp. $\mathbb{R}$), and let $\mathcal{P}$ denote the set of $n \times n$ matrices over $\mathbb{C}$ (resp. $\mathbb{R}$) that can be written as a permutation matrix times a unitary diagonal matrix. Then it is known that the permanent of $A$ satisfies $|\text{perm}(A)| \leq \Vert A \Vert_{2} ^n$ with equality iff $A/ \Vert A \Vert_{2} \in \mathcal{P}$ (where $\Vert A \Vert_2$ is the operator $2$-norm of $A$). We show a stability version of this result asserting that unless $A$ is very close (in a particular sense) to one of these extremal matrices, its permanent is exponentially smaller (as a function of $n$) than $\Vert A \Vert_2 ^n$. In particular, for any fixed $\alpha, \beta > 0$, we show that $|\text{perm}(A)|$ is exponentially smaller than $\Vert A \Vert_2 ^n$ unless all but at most $\alpha n$ rows contain entries of modulus at least $\Vert A \Vert_2 (1 - \beta)$.
(Abstracted from Gynecol Oncol 2018;149:447–454) This historical perspective provides context for the development cytoreductive surgery, and its current role in the treatment of advanced ovarian cancer. It discusses the visionary approach of Joe V.
Gestational trophoblastic diseases are interrelated conditions characterized by abnormal growth of chorionic tissues with various propensities for local invasion and metastasis. Complete mole is a unique conception in that all nuclear DNA is paternally derived and all cytoplasmic DNA is maternally derived. In contrast, partial mole generally has a triploid karyotype, where the extra haploid set of chromosomes is paternally derived: Gestational trophoblastic diseases are characterized by altered expression of several growth regulatory factors and oncogenes. While differences in expression of oncoproteins may be important to the development of gestational trophoblastic disease, the precise molecular changes that are critical to pathogenesis remain unknown.
