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Dysfunctional T cells present in malignant lesions are characterized by a sustained and highly diverse expression of inhibitory receptors, also referred to as immune checkpoints. Yet, their relative functional significance in different cancer types remains incompletely understood. In this study, we provide a comprehensive characterization of the diversity and expression patterns of inhibitory receptors on tumor-infiltrating T cells from patients with non–small cell lung cancer. In spite of the large heterogeneity observed in the amount of PD-1, Tim-3, CTLA-4, LAG-3, and BTLA expressed on intratumoral CD8+ T cells from 32 patients, a clear correlation was established between increased expression of these inhibitory coreceptors and progression of the disease. Notably, the latter was accompanied by a progressively impaired capacity of T cells to respond to polyclonal activation. Coexpression of several inhibitory receptors was gradually acquired, with early PD-1 and late LAG-3/BTLA expression. PD-1 blockade was able to restore T-cell function only in a subset of patients. A high percentage of PD-1hi T cells was correlated with poor restoration of T-cell function upon PD-1 blockade. Of note, PD-1hi expression marked a particularly dysfunctional T-cell subset characterized by coexpression of multiple inhibitory receptors and thus may assist in identifying patients likely to respond to inhibitory receptor–specific antibodies. Overall, these data may provide a framework for future personalized T-cell–based therapies aiming at restoration of tumor-infiltrating lymphocyte effector functions. Cancer Immunol Res; 3(12); 1344–55. ©2015 AACR.

Supplementary Table 1. Clinical data of NSCLC patients. Supplementary Figure 1. Calculation of the iR score. Supp. Figure 2. Activation of PBMC from healthy donors by polyclonal stimulation.

OBJECTIVES: Surgery in octogenarians is performed with acceptable morbidity and mortality. However, little is known about the quality of life (QoL) after surgery especially in octogenarians. The goal of this study was to retrospectively examine quality of life in octogenarian patients. METHODS: Patients aged 80 years and older who had thoracic surgery between June 2013 and November 2015 were asked to recall their QoL before surgery and their present QoL by completing the EORTC QLQ-C30 questionnaire. A statistical significance between pre- and post-operative scores was set at p RESULTS: 79 patients (40 male and 39 female) with a mean age of 84 years (range 80 to 98) were included in the study. 24 patients (30.4%) had undergone a thoracotomy, and 55 patients (69.6%) minimally invasive procedures. 59 (75%) of the patients were ASA III. The median hospitalization time was 13 days and 30-day mortality was 12/79 (15%). Patients aged 85 and older had a higher 30-day mortality. 30 patients answered the questionnaire. The average time between surgery and receipt of the questionnaire was 8.4 months (SD ±4.8 months). There was no significant difference in overall QoL before and after the surgery (p=0.157). There were significant differences in physical functioning (p=0.000), role functioning (p=0.032), cognitive functioning (p=0.002), fatigue (p=0.009), and appetite (p=0.048). CONCLUSIONS: Our results suggest that QoL after thoracic surgery in octogenarians is comparable to preoperative QoL. Since health in elderly people is the most important factor to maintain a good QoL, denial of surgical treatment due only to advanced age, should no longer be acceptable.

T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction.

Dysfunctional T cells present in malignant lesions are characterized by a sustained and highly diverse expression of inhibitory receptors, also referred to as immune checkpoints. Yet, their relative functional significance in different cancer types remains incompletely understood. In this study, we provide a comprehensive characterization of the diversity and expression patterns of inhibitory receptors on tumor-infiltrating T cells from patients with non–small cell lung cancer. In spite of the large heterogeneity observed in the amount of PD-1, Tim-3, CTLA-4, LAG-3, and BTLA expressed on intratumoral CD8+ T cells from 32 patients, a clear correlation was established between increased expression of these inhibitory coreceptors and progression of the disease. Notably, the latter was accompanied by a progressively impaired capacity of T cells to respond to polyclonal activation. Coexpression of several inhibitory receptors was gradually acquired, with early PD-1 and late LAG-3/BTLA expression. PD-1 blockade was able to restore T-cell function only in a subset of patients. A high percentage of PD-1hi T cells was correlated with poor restoration of T-cell function upon PD-1 blockade. Of note, PD-1hi expression marked a particularly dysfunctional T-cell subset characterized by coexpression of multiple inhibitory receptors and thus may assist in identifying patients likely to respond to inhibitory receptor–specific antibodies. Overall, these data may provide a framework for future personalized T-cell–based therapies aiming at restoration of tumor-infiltrating lymphocyte effector functions. Cancer Immunol Res; 3(12); 1344–55. ©2015 AACR.

Background: Aortocoronary bypass graft disease is responsible for long-term failure of autologous vein grafts. The analyses of proliferation and cell type characterisation in human bypass grafts harvested during re-do surgery make it possible to investigate the cellular processes leading to bypass graft failure. Methods: 30 stenotic vein grafts and 25 control veins were explantated during re-do heart surgery procedures. The total area and cell count of the neointima, media and adventitia were calculated computer-assisted. Actively proliferating cells were identified using antibody to Ki-67 and positive cells were determined by double-label immunocytochemistry with SMC α-actin, CD 31 (endothelial cells), CD 68 (macrophages) and CD 45 (T-lymphocytes). Results: Active proliferation was detected in different cell types with an average proliferation index of 0.15%, 0.18% and 0.086% for neointima, media and adventitia. Only 9% of proliferating cells in the neointima were SMC (not identified cells 40%); correspondingly, 14% SMC (not identified cells 33%) were detected in the media. Endothelial cells turned out to be the predominant proliferating cell type in all sections of the vessel wall. Conclusion: Proliferation in our series of stenotic vein grafts occurred at a low level, but was significantly higher compared to native control veins. While proliferation may play an important role in early lesions, our data clearly show low proliferation activity in advanced graft lesions. The identification of proliferating macrophages and T-lymphocytes implicate an additional inflammatory component in the development of human bypass graft disease. Summary: To clarify the role of cellular proliferation in human aortocoronary bypass grafts, we characterized the cellular composition and proliferation index in 30 stenotic saphenous vein grafts in comparison to 25 native veins. Proliferation in our series of stenotic vein grafts occurred at a low level, but was significantly higher compared to native control veins.

Summary Proliferation and differentiation of vascular smooth muscle cells (VSMC) are central events in vascular pathobiology and play a major role in the development of stenotic and restenotic lesions [ 15, 27 ] . The proto-oncogene c-myc and other early cell cycle-regulating genes have been implicated in the induction of cell proliferation and differentiation under diverse pathophysiological conditions [ 11, 13 ] . In the present study we analyzed c-myc mRNAexpression by indirect nonradioactive in situ hybridization technique (NISH) in human stenotic venous bypass grafts (n = 32) retrieved during re-do operations of coronary artery disease and compared the results with 28 native veins (vena saphena magna) from the same patients. Stenotic bypass grafts showed enhanced c-myc expression located predominantly in VSMCin the media and neointima (severity score: ++–+++, 32/32 stenotic veins). In native veins we observed only low levels of – c-myc mRNA(severity score: +, 28/28 native veins), all signals were restricted to endothelial cells of either the innermost intimal layer or of the vasa vasorum. Our in situ hybridization studies demonstrate enhanced mRNAexpression of the proto-oncogene c-myc in stenotic venous bypass grafts. These results suggest that – in analogy to other pathophysiological conditions – c-myc exerts essential regulatory functions in cellular events operative during the initiation and progression of venous bypass graft disease.