Partial, but not Complete, Tumor-Debulking Surgery Promotes Protective Antitumor Memory when Combined with Chemotherapy and Adjuvant Immunotherapy

Broomfield, Steve; Currie, Andrew; Most, Robbert G. van der; Brown, Matthew; Bruggen, Ivonne van; Robinson, Bruce; Lake, Richard

doi:10.1158/0008-5472.can-05-0328

Cited by 73 publications

(59 citation statements)

References 16 publications

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“…In these studies, subsequent immunotherapy, using an agonistic anti-CD40 antibody, cured 80% of tumor-bearing mice, when neither therapy was effective on its own (23). Although this combination of therapies was not effective for very large tumors, the same 80% rate of cure was achieved when partially resected large tumors were then treated with the chemotherapy/immunotherapy combination (24). These experiments suggest that the increased levels of tumor neo-antigen cross-presentation after chemotherapy could be exploited by immunotherapy.…”

Section: Implications For Therapymentioning

confidence: 89%

Cranking the Immunologic Engine with Chemotherapy: Using Context to Drive Tumor Antigen Cross-Presentation towards Useful Antitumor Immunity

et al. 2006

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This review shows how tumor antigen cross-presentation is affected by the major therapeutic modalities including chemotherapy, radiotherapy, and surgery. We argue that this process could affect the way that a tumor works as its own cellular vaccine, and that it is differentially modulated by the choice of treatment. (Cancer Res 2006; 66(2): 601-4) It is estimated that tumors typically accumulate 10 12 or more mutations (1). Even though many of these were already present in the tissue cells from which the tumor originated and only a small proportion occur in the open reading frames of genes expressed by tumor cells, it is inevitable that any given cancer will express at least a few new antigenic determinants that could be recognized by the immune system. Despite this, the immune system rarely stops established tumor growth. It is likely that the same tolerance mechanisms that prevent immune responses against normal tissue cells expressing random mutations also block antitumor responses. Similar to self-antigens, tumor neo-antigens are constitutively and efficiently offered to the immune system through a process known as cross-presentation (2, 3). The fact that tumor neo-antigens are likely to be highly individuated suggests that the most promising approaches to immunotherapy will depend on our ability to turn a tumor into its own cellular vaccine (4). What Is Cross-Presentation?Most cells, including many tumor cells, express MHC class I molecules and can present antigenic peptides to T cells. However, only professional antigen-presenting cells (APC), such as dendritic cells (DC) and macrophages, have the capacity to prime immune responses. These cells acquire antigen from donor cells such as tumor cells, then present the captured antigens via their own MHC class I molecules to CD8 T cells in a process known as antigen crosspresentation (3). However, the precise mechanisms are still controversial (5), and, importantly, the relevance of tumor antigen cross-presentation for the induction of antitumor responses has been questioned (6). In this review, we will discuss the molecular basis for cross-presentation, which we judge to be a constitutive but limited process and describe the basis of the subsequent immune response; cross-priming, when a response is measurable versus cross-tolerance, when it is not. We will argue that crosspresentation of tumor antigens is highly relevant for tumor immunotherapy but that the transition from cross-presentation to crosspriming needs help, either from CD4 T helper cells or via targeted immunotherapy. The combination of chemotherapy with its capacity to alter the rate of cross-presentation with immunotherapy may therefore present an excellent opportunity to achieve this. Which Antigens Are Cross-Presented?The process of antigen cross-presentation was discovered in 1976, when it was shown that immunization with lymphoid cells congenic for minor histocompatibility antigens (7) or with allogeneic or semisyngeneic SV40-transformed cells (8) resulted in the generation of spec...

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Section: Implications For Therapymentioning

confidence: 89%

Cranking the Immunologic Engine with Chemotherapy: Using Context to Drive Tumor Antigen Cross-Presentation towards Useful Antitumor Immunity

et al. 2006

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“…This is, in part, because chemotherapy causes dying tumor cells to release a wave of tumor-associated antigens, which can then enter the antigen-presentation pathway (87,88). In addition, many chemotherapy regimens induce a period of transient lymphopenia and homeostatic recovery, during which T cells seem to be more receptive to breaking tolerance (89)(90)(91)(92).…”

Section: Ido Inhibitors and Chemotherapymentioning

confidence: 99%

Indoleamine 2,3-dioxygenase and tumor-induced tolerance

Munn¹,

Mellor²

2007

J. Clin. Invest.

948

781

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Tumors arise from normal cells of the body through genetic mutation. Although such genetic mutation often leads to the expression of abnormal antigens, the immune system fails to respond effectively to these antigens; that is, it is tolerant of these antigens. This acquired state of tolerance must be overcome for cancer immunotherapy to succeed. Indoleamine 2,3-dioxygenase (IDO) is one molecular mechanism that contributes to tumor-induced tolerance. IDO helps create a tolerogenic milieu in the tumor and the tumor-draining lymph nodes, both by direct suppression of T cells and enhancement of local Treg-mediated immunosuppression. It can also function as an antagonist to other activators of antitumor immunity. Therefore, strategies to block IDO might enhance the effectiveness of tumor immunotherapy.

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“…20 In addition, gemcitabine could affect the negative arm of antitumor immunity by depressing hemagglutinin-specific B cell responses and myeloid suppressor cells. 21 Furthermore, gemcitabine could be successfully combined with immunostimulatory compounds (such as CD40-stimulatory antibodies) to yield synergistic antitumor effects 22,23 Another hint that successful chemotherapy could be associated with improved antigen-specific T lymphocyte responses came from the sequential monitoring of ovarian tumor-specific T-cell responses during cisplatin-based chemotherapy in advanced ovarian carcinoma patients. Only patients in remission displayed potent CD8 þ T-cell responses, whereas patients in progression did not.…”

Section: Inducers Of Immunogenic Cell Deathmentioning

confidence: 99%