Cancer has an impressive ability to evolve multiple processes to evade therapies. While immunotherapies and vaccines have shown great promise, particularly in certain solid tumors such as prostate cancer, they have been met with resistance from tumors that use a multitude of mechanisms of immunosuppression to limit effectiveness. Prostate cancer, in particular, secretes transforming growth factor β (TGF-β) as a means to inhibit immunity while allowing for cancer progression. Blocking TGF-β signaling in T cells increases their ability to infiltrate, proliferate, and mediate antitumor responses in prostate cancer models. We tested whether the potency of chimeric antigen receptor (CAR) T cells directed to prostate-specific membrane antigen (PSMA) could be enhanced by the co-expression of a dominant-negative TGF-βRII (dnTGF-βRII). Upon expression of the dominant-negative TGF-βRII in CAR T cells, we observed increased proliferation of these lymphocytes, enhanced cytokine secretion, resistance to exhaustion, long-term in vivo persistence, and the induction of tumor eradication in aggressive human prostate cancer mouse models. Based on our observations, we initiated a phase I clinical trial to assess these CAR T cells as a novel approach for patients with relapsed and refractory metastatic prostate cancer (ClinicalTrials.gov: NCT03089203).

Summary The effector potential of NK cells is counterbalanced by their sensitivity to inhibition by “self” MHC class I molecules in a process called “education”. In humans, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and human MHC (HLA) mediate NK cell education. In HLA-B* 27:05+ transgenic mice and patients undergoing HLA-mismatched hematopoietic cell transplantation (HCT), NK cells derived from human CD34+ stem cells were educated by HLA from both donor hematopoietic cells and host stromal cells. Furthermore, mature human KIR3DL1+ NK cells gained reactivity after adoptive transfer to HLA-B*27:05+ mice or bone marrow chimeric mice where HLA-B*27:05 was restricted to either the hematopoietic or stromal compartment. Silencing of HLA in primary NK cells diminished NK cell reactivity, while acquisition of HLA from neighboring cells increased NK cell reactivity. Altogether, these findings reveal roles for cell-extrinsic HLA in driving NK cell reactivity upward, and cell–intrinsic HLA in maintaining NK cell education.

Background: Limited information exists on mucocutaneous disease and its relation to course of COVID-19.Objective: To estimate prevalence of mucocutaneous findings, characterize morphologic patterns, and describe relationship to course in hospitalized adults with COVID-19.

KIR3DL1 is a polymorphic inhibitory receptor that modulates natural killer cell activity through interacting with HLA-A and HLA-B alleles that carry the Bw4 epitope. Amino acid polymorphisms throughout KIR3DL1 impact receptor surface expression and affinity for HLA. KIR3DL1/S1 encodes inhibitory and activating alleles, but despite high homology with KIR3DL1, the activating receptor KIR3DS1 does not bind the same ligand. Allele KIR3DL1*009 resulted from a gene recombination event between the inhibitory receptor allele KIR3DL1*001 and the activating receptor allele KIR3DS1*013. This study analyzed the functional impact of KIR3DS1-specific polymorphisms on KIR3DL1*009 surface expression, binding to HLA, and functional capacity. Flow cytometric analysis of primary human NK cells as well as transfected HEK293T cells show that KIR3DL1*009 is expressed at a significantly lower surface density compared to KIR3DL1*001. Using recombinant proteins of KIR3DL1*001, KIR3DL1*009, and KIR3DS1*013 to analyze binding to HLA, we found that while KIR3DL1*009 displayed some evidence of binding to HLA compared to KIR3DS1*013, the binding was minimal compared to KIR3DL1*001 and KIR3DL1*005. Mutagenesis of polymorphic sites revealed that the surface phenotype and reduced binding of KIR3DL1*009 are caused by the combined amino acid polymorphisms at positions 58 and 92 within the D0 extracellular domain. Resulting from these effects, KIR3DL1*009-positive NK cells exhibited less inhibition by HLA-Bw4 positive target cells compared to KIR3DL1*001-positive NK cells. The data from this study contribute novel insight into how KIR3DS1-specific polymorphisms in the extracellular region impact KIR3DL1 surface expression, ligand binding, and inhibitory function.

Introduction: In the past decade, prostate cancer screening decreased, raising the concern of delays in diagnosis and leading to increase in new cases of metastatic prostate cancer. This study evaluated whether these changes may have impacted trends in metastatic prostate cancer incidence and survival. Methods: Metastatic prostate cancer diagnoses from 2008–2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) 18 registries. Age-adjusted incidence rates per 100 000 were calculated by time periods and demographic variables. Two-year all-cause and prostate cancer-specific mortality were calculated for patients diagnosed from 2008–2014, and multivariable Cox proportional hazards models were used to evaluate the impact of demographic and clinical variables. Results: Incidence rates of metastatic prostate cancer increased by 18% from 2008–2009 to 2014–2016 (Incidence rate ratio [IRR]=1.18, 95% confidence interval [CI] 1.14–1.21). This trend was observed across multiple subgroups but was greatest in non-Hispanic Whites and patients living in counties 0–10% below poverty level. There was an overall decreased risk of all-cause and prostate cancer-specific mortality, but unmarried men and men living in counties >20% below poverty level showed statistically significant increased risk of prostate cancer-specific mortality. Conclusions: Non-Hispanic Whites and the wealthiest subgroups had the largest increase in incidence of metastatic prostate cancer since 2008. Despite trends of decreased risk of prostate cancer-specific mortality, we found certain populations experienced increases in mortality risk. Studies exploring the role of socioeconomic factors on screening and access to newer treatments are needed.