• Immunotherapy
• immune cells
• radiation
• tertiary lymphoid structure
• tumour microenvironment

• Humans
• Tumor Microenvironment/immunology
• Tumor Microenvironment/radiation effects
• Tertiary Lymphoid Structures/immunology
• Tertiary Lymphoid Structures/pathology
• Neoplasms/immunology
• Neoplasms/radiotherapy
• Neoplasms/pathology
• Neoplasms/therapy
• Animals
• Radiotherapy/methods
• Dendritic Cells/immunology
• Dendritic Cells/radiation effects

• Animals
• B7-H1 Antigen/metabolism
• Mice
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism
• Humans
• Neoplasm Metastasis
• Cell Line, Tumor
• Female
• Disease Models, Animal
• Chemokine CXCL10/metabolism

• K12 CA139160 NCI NIH HHS
• P30 CA014599 NCI NIH HHS
• T32 GM007019 NIGMS NIH HHS
• R21 CA226582 NCI NIH HHS
• U54 CA274291 NCI NIH HHS
• R01 CA262508 NCI NIH HHS

• Humans
• Radioimmunotherapy
• Combined Modality Therapy
• Neoplasms/radiotherapy
• Neoplasms/drug therapy
• Immunotherapy
• Radiation Dosage

• P50 CA254865 NCI NIH HHS
• P30 CA047904 NCI NIH HHS
• UM1CA186690-06 NIH HHS
• P50 CA097190 NCI NIH HHS
• R01 DE031729 NIDCR NIH HHS
• National Institutes of Health

• Dendritic cells
• Immunotherapy
• Lymph node
• Myeloid
• Radiation
• Tumor

Dendritic cells (DCs) are immune specialized cells playing a critical role in promoting immune response against antigens, and may represent important targets for therapeutic interventions in cancer. DCs can be stimulated ex vivo with pro-inflammatory molecules and loaded with tumor-specific antigen(s). Protocols describing the specific details of DCs vaccination manufacturing vary widely, but regardless of the employed protocol, the DCs vaccination safety and its ability to induce antitumor responses is clearly established. Many years of studies have focused on the ability of DCs to provide overall survival benefits at least for a selection of cancer patients. Lessons learned from early trials lead to the hypothesis that, to improve the efficacy of DCs-based immunotherapy, this should be combined with other treatments. Thus, the vaccine’s ultimate role may lie in the combinatorial approaches of DCs-based immunotherapy with chemotherapy and radiotherapy, more than in monotherapy. In this review, we address some key questions regarding the integration of DCs vaccination with multimodality therapy approaches for cancer treatment paradigms.

• adjuvant therapy
• cancer
• dendritic cells
• immunotherapy

• Adjuvants, Immunologic/therapeutic use
• Animals
• Antigens, Neoplasm/immunology
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Combined Modality Therapy/methods
• Dendritic Cells/immunology
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy, Adoptive/methods
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/radiotherapy
• Progression-Free Survival
• Tumor Escape/drug effects
• Tumor Escape/radiation effects

• Combined treatment
• Guideline
• Hepatocellular carcinoma
• Immunotherapy
• Radiotherapy
• Stereotactic body radiotherapies

• Carcinoma, Hepatocellular/radiotherapy
• Humans
• Liver Neoplasms/radiotherapy
• Neoplasm Recurrence, Local
• Radiosurgery

• Advantages
• COVID-19
• Cancer
• Combination therapy
• Dendritic cell vaccine
• Disadvantages
• Immunotherapy

• Humans
• Neoplasms/radiotherapy
• Radiation Dose Hypofractionation
• Radiotherapy, Conformal
• Radiotherapy, Intensity-Modulated

• CTLA-4
• PD-1
• STING
• TMEM173
• clinical
• immune checkpoint inhibitors
• immunotherapy
• irradiation
• radiation

The successful generation of T cell-mediated immunity for the treatment of cancer has been a major focal point of research. One of the critical strategies of cancer immunotherapy is to efficiently activate antigen-specific CD8 T cells in the immunosuppressive tumor environment. Here, we used transgenic OT-I/CD45.2/Rag^−/− mice as a source of effector CD8 T cells to determine whether irradiation combined with adoptive T cell transfer therapy could improve T cell proliferation and effector function in murine tumor models. Local irradiation combined with adoptive T cell therapy showed a synergistic effect on tumor growth inhibition in mice. Mechanistically, irradiation increased the release of tumor-associated antigens, which facilitated cross-presentation of tumor-associated antigens by dendritic cells and the priming of antigen-specific T lymphocytes. Additionally, irradiation enhanced the homing of the antigen-specific T cells to tumor tissues via the increased release of CCL5, CXCL9, and CXCL11 from tumor cells. Moreover, irradiation enhanced the proliferation and effector function of both adoptively transferred T cells and endogenous antigen-specific T cells. Our findings provide evidence to support that local irradiation enhanced the therapeutic efficacy of adoptive T cell therapy for cancer, indicating that the combination of radiotherapy and adoptive T cell therapy may be a promising strategy for tumor treatment.

• adoptive T cell therapy
• chemokine
• cross-priming
• irradiation
• tumor infiltrating lymphocyte

For more than 25 years, dendritic cell (DC) based vaccination has flashily held promises to represent a therapeutic approach for cancer treatment. While the vast majority of studies has focused on the use of antigen loaded DC, the intratumoral delivery of unloaded DC aiming at in situ vaccination has gained much less attention. Such approach grounds on the ability of inoculated DC to internalize and process antigens directly released by tumor (usually in combination with cell-death-inducing agents) to activate broad patient-specific antitumor T cell response. In this review, we highlight the recent studies in both solid and hematological tumors showing promising clinical results and discuss the main pitfalls and advantages of this approach for endogenous cancer vaccination. Lastly, we discuss how in situ vaccination by DC inoculation may fit with current immunotherapy approaches to expand and prolong patient response.

• cancer immunotherapy
• checkpoint inhibitor combination therapy
• dendritic cell (DC)
• in situ vaccination
• intratumor administration
• monocyte derived dendritic cells (MoDC)

• Oligometastases
• Oligometastatic
• SBRT
• Stereotactic radiotherapy
• Urothelial cancer

• Aged
• Aged, 80 and over
• Bone Neoplasms/secondary
• Bone Neoplasms/surgery
• Brain Neoplasms/secondary
• Brain Neoplasms/surgery
• Disease Progression
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Lung Neoplasms/secondary
• Lung Neoplasms/surgery
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/surgery
• Prognosis
• Radiosurgery/methods
• Retrospective Studies
• Urologic Neoplasms/pathology
• Urologic Neoplasms/surgery

• DC-therapy
• chemotherapy
• combination therapy
• immune checkpoint inhibitors
• radiotherapy

• Kidney
• Renal cell carcinoma
• SBRT

• Carcinoma, Renal Cell/pathology
• Carcinoma, Renal Cell/surgery
• Humans
• Kidney Neoplasms/pathology
• Kidney Neoplasms/surgery
• Prognosis
• Radiosurgery/instrumentation
• Radiosurgery/methods

• T cell activation
• antigen presentation
• antigen uptake
• cytokine secretion
• dendritic cells
• ionizing radiation

• angiogenesis
• extracellular matrix
• immunotherapy
• mesenchymal cells
• myeloid cells
• radiotherapy
• tumor microenvironment
• tumor stroma

• T cells
• cancer immunotherapy
• cross-presentation
• cross-priming
• dendritic cells

Radiation therapy is one of the cornerstones of cancer treatment. In tumor cells, exposure to ionizing radiation (IR) provokes DNA damages that trigger various forms of cell death such as apoptosis, necrosis, autophagic cell death, and mitotic catastrophe. IR can also induce cellular senescence that could serve as an additional antitumor barrier in a context-dependent manner. Moreover, accumulating evidence has demonstrated that IR interacts profoundly with tumor-infiltrating immune cells, which cooperatively drive treatment outcomes. Recent preclinical and clinical successes due to the combination of radiation therapy and immune checkpoint blockade have underscored the need for a better understanding of the interplay between radiation therapy and the immune system. In this review, we will present an overview of cell death modalities induced by IR, summarize the immunogenic properties of irradiated cancer cells, and discuss the biological consequences of IR on innate immune cell functions, with a particular attention on dendritic cells, macrophages, and NK cells. Finally, we will discuss their potential applications in cancer treatment.

• cancer treatment
• immunotherapy
• innate immunity
• ionizing radiation
• tumor cell death

• DC vaccine
• Irradiation
• Microenvironment
• TNF-α
• Tumor-bearing mice

• IFN-gamma
• IL-6
• PD-L1
• checkpoint inhibitor
• fractionated radiotherapy
• glioblastoma
• immunotherapy
• melanoma

• Abscopal effect
• Checkpoint blockade
• SBRT
• SRS

Cross talk between DCs and FBs in understanding the effects of IR in DC function.

Dendritic cell function is modulated by stromal cells, including fibroblasts. Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-α/IL-1β from activated dendritic cells, promoting PGE₂ secretion from stromal fibroblasts. This instructs dendritic cells to up-regulate IL-23, a key Th17-polarizing cytokine. We previously showed that ionizing radiation inhibited IL-23 production by human dendritic cells in vitro. In the present study, we investigated the hypothesis that dendritic cell-fibroblast crosstalk overcomes the suppressive effect of ionizing radiation to support appropriately polarized Th17 responses. Radiation (1–6 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P < 0.0001) without adversely impacting their viability and consequently, inhibited the generation of Th17 responses. Cytokine suppression by ionizing radiation was selective, as there was no effect on IL-1β, -6, -10, and -27 or TNF-α and only a modest (11%) decrease in IL-12p70 secretion. Coculture with fibroblasts augmented IL-23 secretion by irradiated dendritic cells and increased Th17 responses. Importantly, in contrast to dendritic cells, irradiated fibroblasts maintained their capacity to respond to TNF-α/IL-1β and produce PGE₂, thus providing the key intermediary signals for successful dendritic cell-fibroblasts crosstalk. In summary, stromal fibroblasts support Th17-polarizing cytokine production by dendritic cells that would otherwise be suppressed in an irradiated microenvironment. This has potential ramifications for understanding the immune response to local radiotherapy. These findings underscore the need to account for the impact of microenvironmental factors, including stromal cells, in understanding the control of immunity.

• cancer
• cytokine
• immunity

• HPV
• Head and neck cancer
• Immune system
• Immunotherapy
• Tumor immune infiltration

The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs.

The CT26 murine colorectal cancer model was used in this investigation. The inhibition of growth of the tumor and the systemic anti-tumor immune response were measured. The tumor was heated to a core temperature of 42 °C for 30 min. The matured synergetic DCs were intratumorally injected 24 h following mEHT was applied.

mEHT induced significant apoptosis and enhanced the release of heat shock protein70 (Hsp70) in CT26 tumors. Treatment with mEHT-DCs significantly inhibited CT26 tumor growth, relative to DCs alone or mEHT alone. The secondary tumor protection effect upon rechallenging was observed in mice that were treated with mEHT-DCs. Immunohistochemical staining of CD45 and F4/80 revealed that mEHT-DC treatment increased the number of leukocytes and macrophages. Most interestingly, mEHT also induced infiltrations of eosinophil, which has recently been reported to be an orchestrator of a specific T cell response. Cytotoxic T cell assay and ELISpot assay revealed a tumor-specific T cell activity.

This study demonstrated that mEHT induces tumor cell apoptosis and enhances the release of Hsp70 from heated tumor cells, unlike conventional hyperthermia. mEHT can create a favorable tumor microenvironment for an immunological chain reaction that improves the success rate of intratumoral DC immunotherapy.

The online version of this article (doi:10.1186/s12885-015-1690-2) contains supplementary material, which is available to authorized users.

Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.

• adoptive cell therapy
• checkpoint inhibitor
• chemotherapy
• dendritic cell
• immunotherapy
• multimodality
• radiotherapy
• targeted therapy

One prerequisite that radiotherapy (RT) and chemotherapy (CT) result in anti-tumor immune responses is triggering of immunogenic cell death forms such as necroptosis. The latter is inducible by inhibition of apoptosis with the pan-caspase inhibitor zVAD-fmk. The design of multimodal therapies that overcome melanoma's resistance to apoptosis is a big challenge of oncoimmunology. As hints exist that immune stimulation by hyperthermia (HT) augments the efficacy of melanoma therapies and that tumors can be sensitized for RT with zVAD-fmk, we asked whether combinations of RT with dacarbazine (DTIC) and/or HT induce immunogenic melanoma cell death and how this is especially influenced by zVAD-fmk. Necroptosis was inducible in poorly immunogenic B16-F10 melanoma cells and zVAD-fmk generally increased melanoma cell necrosis concomitantly with the release of HMGB1. Supernatants (SNs) of melanoma cells whose cell death was modulated with zVAD-fmk induced an upregulation of the activation markers CD86 and MHCII on macrophages. The same was seen on dendritic cells (DCs), but only when zVAD-fmk was added to multimodal tumor treatments including DTIC. DCs of MyD88 KO mice and DCs incubated with SNs containing apyrase did not increase the expression of these activation markers on their surface. The in vivo experiments revealed that zVAD-fmk decreases the tumor growth significantly and results in a significantly reduced tumor infiltration of Tregs when added to multimodal treatment of the tumor with RT, DTIC and HT. Further, a significantly increased DC and CD8+ T-cell infiltration into the tumor and in the draining lymph nodes was induced, as well as an increased expression of IFNγ by CD8+ T cells. However, zVAD-fmk did not further reduce tumor growth in MyD88 KO mice, mice treated with apyrase or RAG KO mice. We conclude that HMGB1, nucleotides and CD8+ T cells mediate zVAD-fmk induced anti-melanoma immune reactions in multimodal therapy settings.

• Cancer stem cells
• Cancer vaccines
• Cytokine therapy
• Monoclonal antibody therapy
• T cell-based therapy

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.

• abscopal effect
• clinical trials
• immunotherapy
• ionizing radiation
• microenvironment
• radiotherapy
• tumor immunity

Radiation therapy is one of the standard therapeutic modalities for esophageal cancer, achieving its main antitumor efficacy through DNA damage. However, accumulating evidence shows that radiotherapy can substantially alter the tumor microenvironment, particularly with respect to its effects on immune cells. We hypothesized that the immune response elicited by radiotherapy may be as important as the radiation itself for successful treatment. More specifically, immunomodulatory cytokines may enhance the effectiveness of radiotherapy. To investigate this hypothesis, we measured changes in the serum interferon-gamma (IFN-γ) and interleukin-2 (IL-2) concentrations during radiotherapy and compared these modifications with outcomes. We found that serum concentrations of IL-2 and IFN-γ were positively associated with local response to radiotherapy in esophageal cancer. More generally, the intensity of the radiotherapy-elicited immune response was positively associated with local response to radiotherapy in esophageal cancer. Changes in serum IL-2 and IFN-γ concentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin. These results suggest that deciphering the mechanisms of radiotherapy-elicited immune response may help in the development of therapeutic interventions that would enhance the efficacy of radiotherapy and convert some ineffective responses to effective responses.

Patients afflicted with advanced cancers were treated with the intratumoral injection of autologous immature dendritic cells (iDCs) followed by activated T-cell infusion and intensity-modulated radiation therapy (IMRT). A second round of iDCs and activated T cells was then administered to patients after the last radiation cycle. This complete regimen was repeated for new and recurring lesions after 6 weeks of follow-up. One year post therapy, outcome analyses were performed to evaluate treatment efficacy. Patients were grouped according to both the number and size of tumors and clinical parameters at treatment initiation, including recurrent disease after standard cancer therapy, Stage IV disease, and no prior therapy. Irrespective of prior treatment status, 23/37 patients with ≤ 5 neoplastic lesions that were ≤ 3 cm in diameter achieved complete responses (CRs), and 5/37 exhibited partial responses (PRs). Among 130 individuals harboring larger and more numerous lesions, CRs were observed in 7/74 patients that had received prior SCT and in 2/56 previously untreated patients. Some patients manifested immune responses including an increase in CD8⁺CD56⁺ lymphocytes among circulating mononuclear cells in the course of treatment. To prospectively explore the therapeutic use of these cells, CD8⁺ cells were isolated from patients that had been treated with cellular immunotherapy and IMRT, expanded in vitro, and injected into recurrent metastatic sites in 13 individuals who underwent the same immunoradiotherapeutic regimens but failed to respond. CRs were achieved in 34 of 58 of such recurrent lesions while PRs in 17 of 58. These data support the expanded use of immunoradiotherapy in advanced cancer patients exhibiting progressive disease.

• activated T cells
• cancer vaccine
• cytotoxic T lymphocytes
• immature dendritic cells
• intratumoral injection

The aim of our study was to evaluate the prognostic role of immunological microenvironnement in stage II–III CRC patients.

We constructed a tissue microarray from 196 consecutive patients with stage II–III CRC and compared CD3, CD4, CD8, CD57, CD68, CXCL9/MIG, CXCL13, and PPARγ immunoreactivity in tumour samples and their matched non-tumour tissue. We assessed their association with relapse-free survival (RFS; primary endpoint) and overall survival (OS) in multivariate Cox models.

Low densities of CD57+ and CD68+ tumour-infiltrating cells (TIC) independently predicted worse outcomes. A prognostic score combining CD57 (+, > vs −, ⩽2 cells per spot) and CD68 (+, >0 vs −, =0 cells per spot) TIC density discriminated CRC patients at low (CD68+/CD57+), intermediate (CD68+/CD57−), or high (CD68−/CD57−) risk, with hazard ratios for the intermediate-risk and high-risk groups of 2.7 (95% confidence interval (CI): 1.3–5.8) and 9.0 (3.2–25.4) for RFS, and 2.5 (1.2–5.1) and 10.6 (3.8–29.2) for OS, respectively, as compared with the low-risk group. Corresponding 5-year survival rates (95% CI) in the low-, moderate- and high-risk groups were 84% (71–91), 65% (54–74), and 12% (2–47), respectively, for RFS, and 91% (80–96), 76% (66–84), and 25% (7–59), respectively, for OS.

Tumour CD57+ and CD68+ TIC density assessment independently predicts survival in patients with stage II–III CRC. If validated, our score based on a quick, inexpensive, and well-established method such as point counting on diagnostic tissue sections could be used routinely as a prognostic tool in CRC patients.

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4⁺ T cells, CD8⁺ T cells, Treg cells, B cells, NK cells, NK1.1⁺ T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.

• t regulatory cells
• adoptive immunotherapy
• radiation therapy

• Animals
• B-Lymphocytes/radiation effects
• CD11c Antigen/metabolism
• Cell Proliferation/radiation effects
• Dendritic Cells/radiation effects
• Immunotherapy, Adoptive
• Interferon-gamma/biosynthesis
• Interleukin-2/administration & dosage
• Interleukin-2/therapeutic use
• Lymph Nodes/immunology
• Lymph Nodes/transplantation
• Melanoma/immunology
• Melanoma/radiotherapy
• Mice
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• T-Lymphocytes, Regulatory/radiation effects
• Tumor Microenvironment/radiation effects
• Tumor Necrosis Factor-alpha/biosynthesis

• R01 CA082529 NCI NIH HHS
• R56 CA082529 NCI NIH HHS
• T32 CA009672 NCI NIH HHS