T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy.

Cancer immunotherapy has great promise, but is limited by diverse mechanisms used by tumors to prevent sustained antitumor immune responses. Tumors disrupt antigen presentation, T/NK-cell activation, and T/NK-cell homing through soluble and cell-surface mediators, the vasculature, and immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells. However, many molecular mechanisms preventing the efficacy of antitumor immunity have been identified and can be disrupted by combination immunotherapy. Here, we examine immunosuppressive mechanisms exploited by tumors and provide insights into the therapies under development to overcome them, focusing on lymphocyte traffic

Cell therapies in ovarian cancer.

Epithelial ovarian cancer (EOC) is the most important cause of gynecological cancer-related mortality. Despite improvements in medical therapies, particularly with the incorporation of drugs targeting homologous recombination deficiency, EOC survival rates remain low. Adoptive cell therapy (ACT) is a personalized form of immunotherapy in which autologous lymphocytes are expanded, manipulated ex vivo, and re-infused into patients to mediate cancer rejection. This highly promising novel approach with curative potential encompasses multiple strategies, including the adoptive transfer of tumor-infiltrating lymphocytes, natural killer cells, or engineered immune components such as chimeric antigen receptor (CAR) constructs and engineered T-cell receptors. Technical advances in genomics and immuno-engineering have made possible neoantigen-based ACT strategies, as well as CAR-T cells with increased cell persistence and intratumoral trafficking, which have the potential to broaden the opportunity for patients with EOC. Furthermore, dendritic cell-based immunotherapies have been tested in patients with EOC with modest but encouraging results, while the combination of DC-based vaccination as a priming modality for other cancer therapies has shown encouraging results. In this manuscript, we provide a clinically oriented historical overview of various forms of cell therapies for the treatment of EOC, with an emphasis on T-cell therapy

Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era

Genomic technologies have enabled personalized cancer treatments based on the unique molecular aberrations in each person's tumor. T-cell-based immunotherapies may expand the range of therapeutic options for personalized oncology. Here, we discuss the advantages of targeting T cells towards mutations, and the identification and potential therapeutic utilization of mutation-reactive T cell

Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure.

The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can fail in completely eliminating the anomalies, leading to the establishment of chronic pathologies. Prototypical examples of immune system defeat are cancer and Human Immunodeficiency Virus-1 (HIV-1) infection. In both conditions, the immune system is persistently exposed to antigens leading to systemic inflammation, lack of generation of long-term memory and exhaustion of effector cells. This triggers a negative feedback loop where effector cells are unable to resolve the pathology and cannot be replaced due to the lack of a pool of undifferentiated, self-renewing memory T cells. In addition, in an attempt to reduce tissue damage due to chronic inflammation, antigen presenting cells and myeloid components of the immune system activate systemic regulatory and tolerogenic programs. Beside these homologies shared between cancer and HIV-1 infection, the immune system can be shaped differently depending on the type and distribution of the eliciting antigens with ultimate consequences at the phenotypic and functional level of immune exhaustion. T cell differentiation, functionality, cytotoxic potential and proliferation reserve, immune-cell polarization, upregulation of negative regulators (immune checkpoint molecules) are indeed directly linked to the quantitative and qualitative differences in priming and recalling conditions. Better understanding of distinct mechanisms and functional consequences underlying disease-specific immune cell dysfunction will contribute to further improve and personalize immunotherapy. In the present review, we describe relevant players of immune cell exhaustion in cancer and HIV-1 infection, and enumerate the best-defined hallmarks of T cell dysfunction. Moreover, we highlight shared and divergent aspects of T cell exhaustion and T cell activation to the best of current knowledge

TIE-2 expressing monocytes in human cancers.

Tumor-associated macrophages (TAM) are well known as a key player in the tumor microenvironment, which support cancer progression. More recently, a lineage of monocytes characterized by the expression of the TIE-2/Tek angiopoietin receptor identified a subset of circulating and tumor-associated monocytes endowed with proangiogenic activity. TIE-2 expressing monocytes (TEM) were found both in humans and mice. Here, we review the phenotypes and functions of TEM reported so far in human cancer and their potential use as markers of cancer progression and metastasis. Finally, we discuss the therapeutic approaches currently used or proposed to target TEM

Computational KIR copy number discovery reveals interaction between inhibitory receptor burden and survival.

Natural killer (NK) cells have increasingly become a target of interest for immunotherapies. NK cells express killer immunoglobulin-like receptors (KIRs), which play a vital role in immune response to tumors by detecting cellular abnormalities. The genomic region encoding the 16 KIR genes displays high polymorphic variability in human populations, making it difficult to resolve individual genotypes based on next generation sequencing data. As a result, the impact of polymorphic KIR variation on cancer phenotypes has been understudied. Currently, labor-intensive, experimental techniques are used to determine an individual's KIR gene copy number profile. Here, we develop an algorithm to determine the germline copy number of KIR genes from whole exome sequencing data and apply it to a cohort of nearly 5000 cancer patients. We use a k-mer based approach to capture sequences unique to specific genes, count their occurrences in the set of reads derived from an individual and compare the individual's k-mer distribution to that of the population. Copy number results demonstrate high concordance with population copy number expectations. Our method reveals that the burden of inhibitory KIR genes is associated with survival in two tumor types, highlighting the potential importance of KIR variation in understanding tumor development and response to immunotherapy

Biogenesis of HLA Ligand Presentation in Immune Cells Upon Activation Reveals Changes in Peptide Length Preference.

Induction of an effective tumor immunity is a complex process that includes the appropriate presentation of the tumor antigens, activation of specific T cells, and the elimination of malignant cells. Potent and efficient T cell activation is dependent on multiple factors, such as timely expression of co-stimulatory molecules, the differentiation state of professional antigen presenting cells (e.g., dendritic cells; DCs), the functionality of the antigen processing and presentation machinery (APPM), and the repertoire of HLA class I and II-bound peptides (termed immunopeptidome) presented to T cells. So far, how molecular perturbations underlying DCs maturation and differentiation affect the in vivo cross-presented HLA class I and II immunopeptidomes is largely unknown. Yet, this knowledge is crucial for further development of DC-based immunotherapy approaches. We applied a state-of-the-art sensitive MS-based immunopeptidomics approach to characterize the naturally presented HLA-I and -II immunopeptidomes eluted from autologous immune cells having distinct functional and biological states including CD14 <sup>+</sup> monocytes, immature DC (ImmDC) and mature DC (MaDC) monocyte-derived DCs and naive or activated T and B cells. We revealed a presentation of significantly longer HLA peptides upon activation that is HLA allotype specific. This was apparent in the self-peptidome upon cell activation and in the context of presentation of exogenously loaded antigens, suggesting that peptide length is an important feature with potential implications on the rational design of anti-cancer vaccines

Current Opinion and Knowledge on Peritoneal Carcinomatosis: A Survey among a Swiss Oncology Network.

The present survey aimed to evaluate current opinion and practice regarding peritoneal metastasis (PM), satisfaction with available treatment options, and need for new therapeutic approaches. This was a qualitative study conducted between October 2016 and October 2017 in the Réseau Suisse Romand d'Oncologie including 101 members of various oncological specialties. Participants' demographics, current practice, knowledge, and satisfaction regarding available treatment options and need for new treatment options were assessed by semantic differential scales through 33 closed questions with automatic reminders at 4-, 8-, 12-, and 16-week intervals. Twenty-seven participants (27%) completed the survey. Participants were gastrointestinal or gynecologic oncologists and surgeons. Most participants (67%) evaluated their knowledge on PM as moderate, while 22% considered themselves as experts. Clinical usefulness of systemic chemotherapy and hyperthermic intraperitoneal chemotherapy was judged to be moderate to high for PM of ovarian and colorectal origin and moderate to poor for gastric origin. Satisfaction with available treatment options was 6/10 (interquartile range [IQR] 4-7) for ovarian, 5/10 (IQR 3-7) for colorectal, and 3/10 (IQR 1-3) for gastric PM. Treatment strategies varied widely for typical case vignettes. The need for new treatment modalities was rated as 8/10 (IQR 6-10). Usefulness of and satisfaction with available treatment options for PM were rated as moderate at best by oncological experts, and treatment strategies differed importantly among participants. There appears to be a clear need for standardization and new treatment modalities

Deep and lasting response and acquired resistance to BRAFV600E targeting in a low-grade ovarian cancer patient.

The treatment of BRAFV600E mutant melanoma has been revolutionized by BRAF inhibitors. Furthermore, the BRAF/MEK combination has shown further improvement in clinical outcomes in advanced and in adjuvant melanoma patients. In low-grade ovarian tumors, BRAF inhibitor use has been also proposed. Here we present a patient with an excellent, lasting response to BRAF therapy alone. At first progression, after more than two years on BRAF monotherapy, we could not identify any molecular mechanisms explaining resistance. After a switch to dual BRAF/MEK therapy, the patient responded. However, despite the initial response clinical the patient again progressed, this time with the appearance of a KRAS G12C mutation, which could not be overcome by BRAF/MEK therapy. We provide evidence that BRAF inhibitor alone can be highly beneficial in BRAF mutant low-grade ovarian tumors and the resistance mechanisms are similar to that of other BRAF mutant tumors, including in melanoma