Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and "True entropy." Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.

Memory-like Differentiation Enhances NK Cell Responses to Melanoma.

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined. EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNγ and kill melanoma targets in vitro and in vivo using a xenograft model. RESULTS: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNγ production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D- and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells. CONCLUSIONS: Blood NK cells from allogeneic HD or patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials.

Nipple-sparing mastectomies: Clinical outcomes from a single academic institution.

Nipple-sparing mastectomies (NSMs) are increasingly used in the surgical treatment of patients with breast cancer and for prevention of breast cancer. The present study was performed to review the outcomes of patients undergoing NSMs at a single large university setting. A retrospective chart review was performed on all patients undergoing NSMs from 2008-2014. Charts were reviewed for demographic data and patient characteristics. Tumor and breast size, cancer recurrence and complications were also evaluated. Descriptive statistics were utilized to summarize the findings. From 2008-2014, 110 patients underwent 197 NSMs. The mean patient age was 44.4 years (range, 20-77). The average body mass index was 24 (range, 18-47). Breast weight was available for 106 specimens, with a mean weight of 475.5 g (range, 124.1-1,625.0 g). Seventy-three NSMs were performed for cancer and 124 were performed prophylactically. The mean tumor width was 1.38 cm (range, 0-6.0 cm), with an average nipple to tumor distance of 5.87 cm (range, 2.93-10.0 cm). Three (4%) patients required removal of the nipple areolar complex (NAC) due to pathological extension of the tumor. A total of 34 (17.2%) complications occurred, including infections, hematomas and nipple necrosis, with 9 requiring removal of the NAC and 13 requiring removal of the tissue expander or implant. Smokers had a 36.0% (9/25) complication rate, compared with 14.5% (25/172) of nonsmokers (P<0.05). During follow-up, one recurrence was noted, located on the chest wall. There were no recurrences in the NAC group. Therefore, NSMs may safely be performed without compromising oncologic outcomes or increasing complication rates in properly selected patients.

Predictive factors and patterns of recurrence in patients with triple negative breast cancer.

BACKGROUND: We investigated the outcomes of patients with triple negative breast cancer ([TNBC] = estrogen receptor negative, progesterone receptor negative, and HER2 nonamplified). METHODS: We identified 414 patients with stage I-III TNBC treated between 1999 and 2008. Data included patient/tumor characteristics, surgical, systemic, and radiation treatment received, and breast cancer-specific survival. Data were compared using Chi square, Fisher exact test, and logistic regression. A p value <.05 was considered significant. RESULTS: The cohort included 414 patients (mean age 53.8 ± 12.5 years) with a mean follow-up of 68.2 ± 36.4 months. Of 414 patients, 304 (73.4 %) had no evidence of recurrence, while 110 (26.6 %) had recurrent disease, including 19 (17.3 %) with isolated locoregional recurrence, 70 (63.6 %) with isolated distant recurrence, and 21 (19.1 %) with both. Of 91 patients with distant recurrences, lung was most common (n = 38), followed by brain (n = 32), bone (n = 31), and liver (n = 29). Factors significantly associated with recurrence included increasing tumor size, positive nodal status, increasing stage, and type of chemotherapy (adjuvant vs neoadjuvant). After controlling for all potential confounders in multivariate stepwise regression, these same factors were also found to be independent predictors of recurrence. In the survival analysis, these same factors, in addition to receipt of radiation were found to be predictive of survival. CONCLUSIONS: Approximately 25 % of patients with TNBC experienced a locoregional and/or distant recurrence, resulting in greater than 75 % breast cancer-specific mortality for those who experienced a distant recurrence. The lack of targeted therapy for this aggressive breast cancer subtype likely contributed to this finding.