Assessing the Prognostic Significance of Tumor-Infiltrating Lymphocytes in Patients With Melanoma Using Pathologic Features Identified by Natural Language Processing.

Importance: Although tumor-infiltrating lymphocytes (TILs) are an important histopathologic characteristic reflecting host immune response in patients with melanoma, their prognostic value remains controversial. Because manual review of medical records is labor intensive, a survival analysis using a large patient cohort with comprehensive clinical and histopathologic characteristics is lacking. Objective: To assess the prognostic significance of TILs among patients with cutaneous melanoma using a large cohort established through natural language processing (NLP) algorithms. Design, Setting, and Participants: This retrospective cohort study analyzed the medical records of 14 436 patients with cutaneous melanoma at Brigham and Women's Hospital between June 1, 2004, and December 31, 2019. Patients were followed up to death or censored at their last clinical visit. Main Outcome and Measures: The primary outcome was overall survival (OS). Survival analysis was conducted using Kaplan-Meier curves, the log-rank test, and Cox proportional hazards regression analysis. Results: A total of 14 436 patients with cutaneous melanoma were identified in the institution's pathology information system. Using NLP, we established a study cohort of 2624 patients (1462 men [55.7%]; median age, 61 years [interquartile range, 50-72 years]) who had vertical growth phase melanoma with TIL status scored. Absent TILs were identified in 434 patients (16.5%), nonbrisk TILs in 1916 patients (73.0%), and brisk TILs in 274 patients (10.4%). The 5-year survival rate was 71.0% (95% CI, 65.5%-76.9%) among patients with an absence of TILs, 73.8% (95% CI, 71.1%-76.5%) among patients with nonbrisk TILs, and 85.2% (95% CI, 80.0%-90.7%) among patients with brisk TILs. Brisk TILs were significantly associated with improved OS (adjusted hazard ratio, 0.63; 95% CI, 0.42-0.95; P = .03; 14.2% OS advantage at 5 years), and nonbrisk TILs were not associated with improved OS (adjusted hazard ratio, 0.87; 95% CI, 0.68-1.11; P = .25), compared with the absence of TILs. Conclusions and Relevance: This study provides evidence based on a large patient cohort from a single institution that suggests that brisk TILs represent an independent prognostic factor for OS among patients with primary cutaneous melanoma. The study also suggests that NLP is a highly efficient tool to facilitate large-scale analyses that involve free-text clinical data.

Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism.

Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G2/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.