High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy.

A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism that prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert with causing the subversion of anti-tumor immunity in the tumor microenvironment. This redundant immunosuppressive network may pose an impediment to efficacious immunotherapy, thus facilitating tumor progression. Cancer progression clearly documents the failure of immune control over relentless growth of tumor cells. Detailed knowledge of each of these factors responsible for creating an immunosuppressive shield to protect tumor cells from immune destruction is essential for the development of novel immune-based therapeutic interventions of cancer. Multipronged targeted depletion of these suppressor cells may restore production of granzyme B by CD8(+) T cells and increase the number of IFN-γ-producing CD4(+) T cells.

Peripheral blood lymphocyte subsets predict the efficacy of TACE with or without PD-1 inhibitors in patients with hepatocellular carcinoma: a prospective clinical study.

Background: Although peripheral blood lymphocyte subsets, particularly PD-1+ T cells, are promising prognostic indicators for patients with cancer. However, their clinical significance remains unclear. Methods: We prospectively enrolled 157 patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization combined with or without PD-1 inhibitors. Twenty peripheral lymphocyte subsets and cytokines were analyzed. We analyzed the differences in PD-1+ T cells between patients treated with and without PD-1 inhibitors and their associations with tumor response, survival prognosis, and clinical features. Results: We found that the baseline CD8+PD-1+ and CD4+PD-1+ T-cell frequencies in patients who had received PD-1 inhibitors were lower than those in patients who had not received PD-1 inhibitors (p < 0.001). In the former patients, there were no differences in PD-1+ T-cell frequencies between the responder and non-responder subgroups (p > 0.05), whereas in the latter patients, the levels of CD8+PD-1+ T cells, CD4+PD-1+ T cells, and CD8+PD-1+/CD4+PD-1+ ratio did not predict tumor response, progression-free survival (PFS), or overall survival (OS) (p>0.05). Furthermore, in multivariate analysis of patients treated with or without PD-1 inhibitors revealed that the levels of CD8+CD38+ T cells (OR = 2.806, p = 0.006) were associated with tumor response, whereas those of CD8+CD28+ T cells (p = 0.038, p = 0.001) and natural killer (NK) cells (p = 0.001, p = 0.027) were associated with PFS and OS. Although, these independent prognostic factors were associated with progressive tumor characteristics (p<0.05), with the exception of CD8+CD28+ T cells, changes in these factors before and after treatment were unassociated with tumor response (p > 0.05). Conclusion: Circulating CD8+CD38+ T cells, CD8+CD28+ T cells, and NK cells were identified as potential prognostic factors for tumor response and survival in patients with HCC. Contrastingly, although PD-1 inhibitors can effectively block the T cell PD-1 receptor, the baseline PD-1+ T-cell frequencies and changes in the frequency of these cells have limited prognostic value.

ES-SCLC Patients with PD-L1+ CTCs and High Percentages of CD8+PD-1+T Cells in Circulation Benefit from Front-Line Immunotherapy Treatment.

SCLC is an aggressive cancer type with high metastatic potential and bad prognosis. CTCs are a valuable source of tumor cells in blood circulation and are among the major contributors to metastasis. In this study we evaluated the number of CTCs that express PD-L1 in treatment-naïve ES-SCLC patients receiving ICI in a front-line setting. Moreover, we explored the percentages of different immune T-cell subsets in circulation to assess their potential role in predicting responses. A total of 43 patients were enrolled-6 of them with LS-SCLC, and 37 with ES-SCLC disease. In addition, PBMCs from 10 healthy donors were used as a control group. Different T-cell subtypes were examined through multicolor FACS analysis and patients' CTCs were detected using immunofluorescence staining. SCLC patients had higher percentages of PD-1-expressing CD3+CD4+ and CD3+CD8+ T-cells, as well as elevated PD-1 protein expression compared to healthy individuals. Additionally, in ES-SCLC patients, a positive correlation between CD3+CD8+PD-1+ T-cells and PD-L1+ CTCs was detected. Importantly, patients harboring higher numbers of CD3+CD8+PD-1+ T-cells together with PD-L1+CTCs had a survival advantage when receiving front-line immunotherapy. Thus, this study proposes, for first time possible, immune cell-CTCs interaction, as well as a potential novel clinical biomarker for ICI responses in ES-SCLC patients.

Immunomodulatory Activity of VEGF in Cancer.

The ability of tumor cells to escape tumor immunosurveillance contributes to cancer development. Factors produced in the tumor microenvironment create "tolerizing" conditions and thereby help the tumor to evade antitumoral immune responses. VEGF-A, already known for its major role in tumor vessel growth (neoangiogenesis), was recently identified as a key factor in tumor-induced immunosuppression. In particular, VEGF-A fosters the proliferation of immunosuppressive cells, limits T-cell recruitment into tumors, and promotes T-cell exhaustion. Antiangiogenic therapies have shown significant efficacy in patients with a variety of solid tumors, preventing tumor progression by limiting tumor-induced angiogenesis. VEGF-targeting therapies have also been shown to modulate the tumor-induced immunosuppressive microenvironment, enhancing Th1-type T-cell responses and increasing tumor infiltration by T cells. The immunomodulatory properties of VEGF-targeting therapies open up new perspectives for cancer treatment, especially through strategies combining antiangiogenic drugs with immunotherapy. Preclinical models and early clinical studies of these combined approaches have given promising results.

Large B-cell lymphomas poor in B cells and rich in PD-1+ T cells can mimic T-cell lymphomas.

OBJECTIVES: To characterize the clinicopathologic features of cases of large B-cell lymphomas, poor in B cells and densely rich in programmed cell death-1 (PD-1)+ reactive T cells, which can mimic T-cell lymphomas. METHODS: A single-institute retrospective review of cases between 2010 and 2013 was performed. RESULTS: Of 178 cases of large B-cell lymphomas, eight cases of large B-cell lymphomas poor in B cells and diffusely rich in sheets of PD-1+ T cells were identified. These cases either were initially misdiagnosed as a T-cell lymphoma or substantiated a broader differential diagnosis including a T-cell lymphoma. Five cases were T-cell histiocyte-rich large B-cell lymphomas, and three cases were diagnosed as large B-cell lymphomas rich in T cells. In three of these cases, a subset of the PD-1+ T cells showed either morphologic nuclear atypia or atypical expression of T-cell antigens on flow cytometry and/or immunohistochemistry. CONCLUSIONS: Large B-cell lymphomas poor in B cells and rich in T cells can have diffuse sheets of reactive PD-1+ T cells, some with atypical morphologic and immunophenotypic features mimicking a T-cell lymphoma. Careful assessment of the immunoarchitecture and background inflammatory and stromal cells can prevent erroneous diagnoses in such cases.