Programmed Death Ligand 2 in Cancer-Induced Immune Suppression

Inhibitory molecules of the B7/CD28 family play a key role in the induction of immune tolerance in the tumor microenvironment. The programmed death-1 receptor (PD-1), with its ligands PD-L1 and PD-L2, constitutes an important member of these inhibitory pathways. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed and are undergoing human clinical testing. However, PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. Here, we review the literature on the immunobiology of PD-L2, particularly on its possible roles in cancer-induced immune suppression and we discuss the results of recent studies targeting PD-L2 in cancer

Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action

Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The diverse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of individual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment

A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients

Contains fulltext : 87604.pdf (publisher's version ) (Closed access)BACKGROUND: Dendritic cell (DC) vaccination has been shown to induce anti-tumour immune responses in cancer patients, but so far its clinical efficacy is limited. Recent evidence supports an immunogenic effect of cytotoxic chemotherapy. Pre-clinical data indicate that the combination of chemotherapy and immunotherapy may result in an enhanced anti-cancer activity. Most studies have focused on the immunogenic aspect of chemotherapy-induced cell death, but only few studies have investigated the effect of chemotherapeutic agents on the effector lymphocytes of the immune system. METHODS: Here we investigated the effect of treatment with oxaliplatin and capecitabine on non-specific and specific DC vaccine-induced adaptive immune responses. Stage III colon cancer patients receiving standard adjuvant oxaliplatin/capecitabine chemotherapy were vaccinated at the same time with keyhole limpet haemocyanin (KLH) and carcinoembryonic antigen (CEA)-peptide pulsed DCs. RESULTS: In 4 out of 7 patients, functional CEA-specific T-cell responses were found at delayed type hypersensitivity (DTH) skin testing. In addition, we observed an enhanced non-specific T-cell reactivity upon oxaliplatin administration. KLH-specific T-cell responses remained unaffected by the chemotherapy, whereas B-cell responses were diminished. CONCLUSION: The results strongly support further testing of the combined use of specific anti-tumour vaccination with oxaliplatin-based chemotherapy

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumors displayed a transcriptional signature consistent with increased activity of nuclear receptors PPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma

Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

We thank the Rockefeller University Center for Clinical and Translational Science (UL1 TR000043 NCATS, NIH) for technical support

Dendritic cells in cancer immunology and immunotherapy

Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.S.K.W. is supported by a European Molecular Biology Organization Long- Term Fellowship (grant ALTF 438– 2016) and a CNIC–International Postdoctoral Program Fellowship (grant 17230–2016). F.J.C. is the recipient of a PhD ‘La Caixa’ fellowship. Work in the D.S. laboratory is funded by the CNIC, by the European Research Council (ERC Consolidator Grant 2016 725091), by the European Commission (635122-PROCROP H2020), by the Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R), by the Comunidad de Madrid (B2017/BMD-3733 Immunothercan- CM), by FIS- Instituto de Salud Carlos III, MCNU and FEDER (RD16/0015/0018-REEM), by Acteria Foundation, by Atresmedia (Constantes y Vitales prize) and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III, the MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (SEV-2015-0505).S

Restoration of defective cross-presentation in tumors by gemcitabine

Tumor antigen cross-presentation by dendritic cells (DCs) to specific CD8(+) T cells is central to antitumor immunity. Although highly efficient in draining lymph nodes, it is defective within the tumor site itself. Importantly, an immunogenic chemotherapy, gemcitabine, reverses this defect, allowing the potential re-stimulation of cytotoxic T lymphocytes within tumor sites