Location, location, location: CD103 demarcates intraepithelial, prognostically favorable CD8 tumor-infiltrating lymphocytes in ovarian cancer.

Although high levels of tumor-infiltrating lymphocytes (TILs) generally correlate with good prognosis in high-grade serous ovarian cancer (HGSC) patients, little is known about the phenotype or specificity of these cells. We have recently demonstrated that TIL expressing the intra-epithelial lymphocyte marker CD103 (official name, integrin α, ITGAE) abundantly infiltrate HGSCs, strongly correlating with increased disease-specific survival.

Tumor vascularity in ovarian cancer: T cells need breathing room.

Tumor-infiltrating lymphocytes (TILs) are crucial for effective antitumor responses. However, hypoxia can skew T-cell differentiation and function, thereby perturbing TILs. We have demonstrated that TILs and their immune function are associated with tumor vascularization.

Individual investigator profiles of biospecimen use in cancer research.

Background: Establishing targets for case accrual is an important component of a strategic plan for a biobank. We have previously assessed overall patterns of biospecimen use in cancer research publications in selected journals. Here we extend this analysis to consider patterns of biospecimen use in relation to cancer research programs developed by individual investigators.

Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade serous ovarian carcinoma.

Background: When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer.

Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer.

Purpose: Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment.

Experimental Design: Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor.

Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer.

Background: The presence of CD8(+) tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in high-grade serous ovarian cancer (HGSC) and other epithelial cancers. Survival is most strongly associated with intraepithelial versus intrastromal CD8(+) TILs; however, the mechanisms that promote the intraepithelial localization of TILs remain poorly understood. We hypothesized that intraepithelial CD8(+) TILs, like normal mucosal intraepithelial lymphocytes, might express CD103, a subunit of αE/β7 integrin, which binds E-cadherin on epithelial cells.

Dysregulated hematopoiesis caused by mammary cancer is associated with epigenetic changes and hox gene expression in hematopoietic cells.

Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis.

Oncostatin-M promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer.

Cancer stem cell (CSC) biology and the epithelial-to-mesenchymal transition (EMT) are thought to be mechanistically linked and may be key components of cancer development and progression. However, stimuli that induce EMT and CSC-like features ('stemness') are poorly defined. We and others have shown that the inflammatory cytokine oncostatin-M (OSM) mediates phenotypic changes in breast cancer that are consistent with EMT and dedifferentiation, including enhanced migration and loss of hormone receptors.

Tumor-infiltrating B cells and T cells: Working together to promote patient survival.

We recently reported a novel cooperative relationship between tumor-infiltrating B cells and CD8(+) T cells in ovarian cancer, leading to increased patient survival. Here, we discuss the mechanisms whereby B cells might enhance cellular immunity, including serving as antigen-presenting cells, organizing tertiary lymphoid structures and secreting polarizing cytokines. The enhancement of both B and T-cell responses may result in more potent and sustained antitumor immunity.

Biospecimen use correlates with emerging techniques in cancer research: impact on planning future biobanks.

The average cohort size for tissue biospecimens used in cancer research studies has increased significantly over the last 20 years. To understand some of the factors behind changes in biospecimen use, we examined cancer research publications to characterize the relationship between specific assay techniques and biospecimen formats and products. We assessed a representative cross section of 378 publications in the journal Cancer Research that used tissue biospecimens, selected from 6 intervals between 1988 and 2010.

Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer.

Background: Regulatory T cells (Tregs) are commonly identified by expression of the transcription factor FOXP3 and are conventionally thought to promote cancer progression by suppressing anti-tumour immune responses. We examined the relationship between FOXP3(+) tumour-infiltrating lymphocytes (TIL) and prognosis in oestrogen receptor (ER)-negative breast cancer, a tumour subtype with poor clinical outcome in which TIL are abundant.

Methods: FOXP3(+) and CD8(+) TIL were assessed by immunohistochemistry in a cohort of 175 ER- breast tumours.

The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer.

Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation-induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule-associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer.

Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity.

Tumors and the immune system are intertwined in a competition where tilting the fine balance between tumor-specific immunity and tolerance can ultimately decide the fate of the host. Defensive and suppressive immunological responses to cancer are exquisitely sensitive to metabolic features of rapidly growing tumors, such as hypoxia, low nutrient availability, and aberrant growth factor signaling. As a result, clinical therapies impacting these properties change the in situ antitumor immune response by virtue of disrupting the tumor environment.

CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer.

Purpose: Tumor-infiltrating lymphocytes (TIL), in particular CD8(+) T cells and CD20(+) B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8(+) TIL can mediate direct cytolytic activity against tumors, the role of CD20(+) TIL is poorly understood. Here, we investigate the possible contributions of CD20(+) TIL to humoral and cellular tumor immunity.

Implications of therapy-induced selective autophagy on tumor metabolism and survival.

Accumulating evidence indicates that therapies designed to trigger apoptosis in tumor cells cause mitochondrial depolarization, nuclear damage, and the accumulation of misfolded protein aggregates, resulting in the activation of selective forms of autophagy. These selective forms of autophagy, including mitophagy, nucleophagy, and ubiquitin-mediated autophagy, counteract apoptotic signals by removing damaged cellular structures and by reprogramming cellular energy metabolism to cope with therapeutic stress. As a result, the efficacies of numerous current cancer therapies may be improved by combining them with adjuvant treatments that exploit or disrupt key metabolic processes induced by selective forms of autophagy.

The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature.

CD8+ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3+ T cells to enhance tumor immunity.

Absolute lymphocyte count is associated with survival in ovarian cancer independent of tumor-infiltrating lymphocytes.

Background: The immune system strongly influences outcome in patients with ovarian cancer. In particular, the absolute lymphocyte count in peripheral blood (ALC) and the presence of tumor-infiltrating lymphocytes (TIL) have each been associated with favourable prognosis. However, the mechanistic relationships between ALC, TIL and prognosis are poorly understood.

Oncostatin M suppresses oestrogen receptor-α expression and is associated with poor outcome in human breast cancer.

The most important clinical biomarker for breast cancer management is oestrogen receptor alpha (ERα). Tumours that express ER are candidates for endocrine therapy and are biologically less aggressive, while ER-negative tumours are largely treated with conventional chemotherapy and have a poor prognosis. Despite its significance, the mechanisms regulating ER expression are poorly understood.

When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen.

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism.

Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer.

Introduction: Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.

Methods: The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low.

A proposed schema for classifying human research biobanks.

Human research biobanks have rapidly expanded in the past 20 years, in terms of both their complexity and utility. To date there exists no agreement upon classification schema for these biobanks. This is an important issue to address for several reasons: to ensure that the diversity of biobanks is appreciated, to assist researchers in understanding what type of biobank they need access to, and to help institutions/funding bodies appreciate the varying level of support required for different types of biobanks.

A novel, broad spectrum therapeutic HPV vaccine targeting the E7 proteins of HPV16, 18, 31, 45 and 52 that elicits potent E7-specific CD8T cell immunity and regression of large, established, E7-expressing TC-1 tumors.

Persistent infection by high risk genotypes of human papillomavirus (HPV) is the cause of cervical cancer, which remains one of the most common cancers among women worldwide. In addition, there is a growing appreciation that high risk HPVs are associated with a number of other cancers including anogenital cancers as well as a subset of head and neck cancers. Recently, prophylactic HPV vaccines targeting the two most prevalent high risk HPVs (HPV16 and HPV18) have been deployed in large-scale vaccination campaigns.

Intratumoral Immune Responses Can Distinguish New Primary and True Recurrence Types of Ipsilateral Breast Tumor Recurrences (IBTR).

Ipsilateral breast tumor recurrence (IBTR) is an increasingly common clinical challenge. IBTRs include True Recurrences (TR; persistent disease) and New Primaries (NP; de novo tumors), but discrimination between these is difficult. We assessed tumor infiltrating leukocytes (TIL) as biomarkers for distinguishing these types of IBTR using primary tumors and matched IBTRs from 24 breast cancer patients, half of which were identified as putative TRs and half as NPs using a previously reported clinical algorithm.

Profound CD8+ T cell immunity elicited by sequential daily immunization with exogenous antigen plus the TLR3 agonist poly(I:C).

The development of vaccines that elicit robust CD8(+) T cell immunity has long been a subject of intense investigation. Although whole exogenous protein has not historically been considered as useful for eliciting CD8(+) T cell immunity, we report herein that whole, protein antigen is capable of eliciting profound levels of CD8(+) T cell immunity if it is administered via repeated, daily subcutaneous immunization in combination with the TLR3 agonist poly(I:C). Mice immunized for four consecutive days with 100 μg of either whole exogenous OVA or whole HPV16 E7 protein combined with 10 μg of poly(I:C) mounted remarkable antigen-specific CD8(+) T cell responses as measured by tetramer staining and ELISPOT analysis of splenocytes and peripheral blood, with up to 30% of peripheral CD8(+) T cells being antigen specific within 7-8 days of vaccination.