Prostate cancer, tumor immunity and a renewed sense of optimism in immunotherapy

Rigamonti, Nicolò; Bellone, Matteo

doi:10.1007/s00262-012-1216-6

Cited by 20 publications

(13 citation statements)

References 159 publications

(197 reference statements)

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“…So far, either chemotherapy, surgery or radiotherapy have been combined with either one of active immunotherapy and/or adoptive T cell therapy, checkpoint blockade strategies or drugs that modify the vascularization and metabolism of the tumor (38, 50, 116, 176–178), thus improving distribution and synergistic anti-cancer activity of drugs and T cells. A step forward will be to carefully devise multiple targeted therapies that simultaneously or subsequently attack tumor cells and the diverse aspects of the tumor microenvironment, and yet preserve the function of organs not involved by the neoplasm.…”

Section: Discussionmentioning

confidence: 99%

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Bellone¹,

Calcinotto²

2013

Front. Oncol.

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137

117

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The tumor is a hostile microenvironment for T lymphocytes. Indeed, irregular blood flow, and endothelial cell (EC) anergy that characterize most solid tumors hamper leukocyte adhesion, extravasation, and infiltration. In addition, hypoxia and reprograming of energy metabolism within cancer cells transform the tumor mass in a harsh environment that limits survival and effector functions of T cells, regardless of being induced in vivo by vaccination or adoptively transferred. In this review, we will summarize on recent advances in our understanding of the characteristics of tumor-associated neo-angiogenic vessels as well as of the tumor metabolism that may impact on T cell trafficking and fitness of tumor infiltrating lymphocytes. In particular, we will focus on how advances in knowledge of the characteristics of tumor ECs have enabled identifying strategies to normalize the tumor-vasculature and/or overcome EC anergy, thus increasing leukocyte-vessel wall interactions and lymphocyte infiltration in tumors. We will also focus on drugs acting on cells and their released molecules to transiently render the tumor microenvironment more suitable for tumor infiltrating T lymphocytes, thus increasing the therapeutic effectiveness of both active and adoptive immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Bellone¹,

Calcinotto²

2013

Front. Oncol.

Self Cite

137

117

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“…Taken together and within the limitations of heterotopic transplantable models, these results suggest not only that tumor-specific CTLs are involved in prostate cancer immunoediting in TRAMP mice already at the level of CSCs, but also that an NK cell-mediated immunosurveillance against CSC might be active in this model. Thus, strategies aimed at increasing the antitumor functions of innate immune effects, such as administration of specific cytokines, 43 should promote the eradication of prostate tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Because CSCs can be targeted by NK as well as T cells and express TAAs that are already exploited in the clinics, one may argue that traditional anticancer vaccines should target both CSCs and more differentiated tumor cells. So why have anticancer vaccines a limited efficacy in patients? 43 At least in part, this might depend on the poor general status of patients that have been enrolled so far in clinical trials, and/or on previous therapies that may have irreversibly undermined the patient’s immune system. The tumor itself may also establish a robust state of local and systemic immunosuppression 43 .…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses

et al. 2013

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According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSCs can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice expressed prostate cancer-associated antigens, MHC Class I and II molecules as well as ligands for natural killer (NK) cell receptors. Indeed, CSC were targets for both NK cell- and CTL-mediated cytotoxicity, both in vitro and in vivo. The administration of dendritic cells pulsed with irradiated CSCs induced a tumor-specific immune response that was more robust than that induced by dendritic cells pulsed with differentiated tumor cells, delayed tumor growth in mice challenged with prostate CSCs and caused tumor regression in TRAMP mice. Thus, CSC are targeted by both innate and adaptive immune responses and might be exploited for the design of novel immunotherapeutic approaches against cancer.

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“…Thus, vaccination seems to be critical, but boosting strategies of subjects with residual disease or with tumor recurrence, should be carefully revisited. Although cancer vaccines have limited efficacy in patients with advanced cancer (9,47), patients defined as high-risk after radical prostatectomy (48) might benefit from this treatment (49). Should they be considered in a preventive or therapeutic setting?…”

Section: Discussionmentioning

confidence: 99%

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

et al. 2013

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Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumorspecific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-g-competent memory CD8þ T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease. Cancer Res; 73(12); 3545-54. Ó2013 AACR.

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Prostate cancer, tumor immunity and a renewed sense of optimism in immunotherapy

Cited by 20 publications

References 159 publications

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

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