Microenvironment to Immunotherapy Clinical Trials

There are two principal implications of the results uncovered by studies of the metastatic melanoma tumor microenvironment. First, it is plausible to perform pretreatment tumor biopsies to examine features of the tumor microenvironment that may correlate with clinical response to melanoma vaccines. Identifying a molecular signature linked to clinical outcome should ultimately be able to guide patient selection for such studies. We have performed such a prospective analysis Fig. 4.3 Tumor...

Evidence for Systemic Immune Deviation in Cancer

In patients with cancer, alterations also occur in systemic antitumor immunity 56, 131, 190, 192 . In a tumor-bearing host, dissemination of antigens released from the growing (shed or secreted antigens) or dying (apoptotic necrotic debris) tumor cells assures their access to APC and allows for the cross-priming of immune effector cells in lymphoid tissues draining the site of the tumor. It is likely that the composition, number and the state of activation differentiation of the immune...

Cancer Stem Cells and their Dr Jekyll and Mr Hyde Antigens

The cancer stem cell hypothesis of tumor development has recently been proposed for many types of cancer 116 and therefore has replaced the older stochastic model of cancer development. It provides a likely explanation for failed cancer treatments and recurrences that are now considered to be due to therapy resistant cancer stem cells. Furthermore, this model is supported by the observations that cancer may arise from embryonic cells, as observed in childhood tumors, or through activation of...

Chemosensitizing Drugs as Immunosensitizing Agents

Even though most advanced malignant tumor cells are resistant to chemotherapeutic drugs and cytotoxic immune cells, in many instances, low levels of the same or different drugs could sensitize resistant tumor cells to immune-mediated apoptosis 33-36 . Sensitization by chemotherapeutic drugs has also been documented in cells that express the drug efflux pump, p-glycoprotein 37 . These observations suggest that the sensitizing property of chemotherapeutic drugs may be distinct from their direct...

Spontaneous Systemic T Cell Responses in Cancer Patients

During the last few years, numerous studies have emerged that clearly demonstrate the spontaneous induction of functional, TAA-specific T cell responses in many tumor patients. We observed in the bone marrow of mice bearing disseminated lymphoma cells TAA-reactive CD8 T cells that conferred protection against (i) expansion of tumor cells in situ as well as (ii) against the formation of distant metastases 6, 7 . Based on this observation, we analyzed the possibility that the presence of tumor...

Dr Jekyll MUC1 is a Tumor Antigen Targeted by Immune Surveillance

In normal epithelia MUC1 expression is found in small amounts and restricted to the apical cell surface. However, in > 80 of most premalignant lesions that are precursors to cancer and other adenocarcinomas 28, 37 , MUC1 expression is highly up-regulated for instance in breast cancer it is expressed up to 10-fold higher than in normal cells 38 . MUC1 expressed on tumor cells displays striking alterations with respect to shortened glycan chains (Tn-antigen (GalNAc1-O-S T) and...

Tumor Microenvironment under the Magnifying Glass A New Challenge to Cancer Immunologists

The theory of immunological surveillance against cancer has been introduced half a century ago by McFarlane Burnet and Lewis Thomas. Despite extensive research to validate and generalize this concept, approaches to intervene in cancer by immunological means has led to more disappointments than successes, more doubts than convictions. Is this concept still valid If the question addresses the possibility that cancer cells induce protective immunity sufficient to enact tumor rejection, the answer...

Candidate Cancer Stem Cell Markers

Cancer stem cells represent a very small percentage of highly malignant cells, probably less than 1 within the bulk of mature, differentiated tumor cells. Self-renewal and multipotency have been used as the gold standard assay to identify cancer stem cells. Overexpression of multi drug-resistance proteins in cancer stem cells and therefore their capability to efflux the fluorescent DNA-binding dyes Hoechst 33342 or rhodamine 123 that can be monitored by flow cytometry, has been used as...

The Tumor Microenvironment and the Induction and Function of Tumor Specific T Cells

Tumor Microenvironment Inflammatory

It has become apparent that development of cancer is not simply a result of genetic alterations within the tumor but is associated with complex changes in host stromal, endothelial and inflammatory cells 42 The development of an invasive cancer involves increasing release of intracellular endogeneous danger signals from necrotic cells which is associated with the formation of a disordered tumor microenvironment. Such environment is characterized by promotion of angiogenesis and stromal...

Cancer Treat Res 2006 130 103-124

Aalamian M, Pirtskhalaishvili G, Nunez A, Esche C, Shurin GV, Huland E, Huland H, Shurin MR. Human prostate cancer inhibits maturation of monocyte-derived dendritic cells. Prostate, 46 68-75, 2001. 2. Abrahams VM, Straszewski SL, Kamsteeg M, Hanczaruk B, Schwartz PE, Rutherford TJ, Mor G. Epithelial ovarian cancer cells secrete Fas ligand. Cancer Res., 63 5573-5581, 2003. 3. Adriance MC, Gendler SJ. Downregulation of Mucl in MMTV-c-Neu tumors. Oncogene, 23 3 697-705, 2004. 4. Aggarwal BB....