Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy

Our plain-English summary of Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy, by A.M. McDonnell, W.J. Lesterhuis, A. Khong, et al (European Journal of Immunology, 2015).

The study

• Authors: A.M. McDonnell, W.J. Lesterhuis, A. Khong, A.K. Nowak, R.A. Lake, A.J. Currie, B.W. Robinson
• Journal: European Journal of Immunology
• Published: 2015;45(1):49-59
• Cited by: 69 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8(+) T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b(+) DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take up, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In plain English

This was a laboratory study in mice. It did not study people or asbestos exposure. The authors grew a mouse mesothelioma cell line, AB1-HA, under the skin of BALB/c mice. The tumor cells carried a marker protein (HA) from influenza virus, so the authors could track immune cells that recognize it. They studied dendritic cells, which are immune cells that show pieces of tumor to killer T cells. T cells injected into the tumors multiplied in nearby lymph nodes but were never seen multiplying inside the tumors (under 5%). Dendritic cells taken from the tumors could not activate these T cells, while dendritic cells from the tumor-draining lymph nodes could. The tumor dendritic cells could take up and break down protein, but they were worse than normal lymph node dendritic cells at presenting it to T cells. After one dose of the chemotherapy drug gemcitabine (120 mg/kg), tumor dendritic cells did activate the T cells. The authors concluded that gemcitabine increases the presentation of tumor material by dendritic cells inside the tumor.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse tumor model with laboratory tests on immune cells taken from tumors and lymph nodes)
• Who was studied: BALB/c mice (from the Animal Resources Centre, Western Australia) carrying AB1-HA mouse mesothelioma tumors grown under the skin of the flank. The tumors carry influenza virus HA as a marker. HA-specific T cells came from CL4 TCR-transgenic mice. Groups were small (for example n = 3 to 6 or n = 8 to 9 mice).
• Exposure: No asbestos or fiber exposure was studied. The treatment tested was gemcitabine chemotherapy, 120 mg/kg into the abdominal cavity, given once on day 19 after tumor inoculation and compared with saline.
• Main results:
  • HA-specific CL4 T cells injected into tumors proliferated in the tumor-draining lymph nodes (more than 60% in the draining axillary node at all time points). They were never seen proliferating within the tumors (below 5%).
  • Most tumor-infiltrating dendritic cells were CD11b+CD205+ (more than 75%) and showed a semimature phenotype.
  • Dendritic cells purified from tumors did not induce CL4 T-cell proliferation. Dendritic cells from tumor-draining lymph nodes of the same mice did.
  • When HA peptide was added directly, tumor dendritic cells and normal lymph node dendritic cells presented it similarly, with the same sensitivity limit of 10 pg/mL.
  • Maturing tumor dendritic cells in the lab with LPS, polyI:C, anti-CD40 antibody or IFN-gamma did not restore their ability to activate CL4 T cells.
  • Tumor dendritic cells processed the test protein DQ-OVA. Their fluorescence (MFI) rose from 26.3 at 4°C to 1492 at 37°C, compared with MFIs of 80 (normal lymph node dendritic cells) and 63 (splenic dendritic cells) at 37°C.
  • Tumor dendritic cells cross-presented HA protein. The T-cell proliferation they induced was significantly lower than with normal lymph node dendritic cells, but only at the highest HA protein concentration (p = 0.019).
  • Tumor dendritic cells from gemcitabine-treated mice induced CL4 T-cell proliferation, with increased IFN-gamma production. Tumor dendritic cells from saline-treated mice did not. Gemcitabine did not change cross-presentation by dendritic cells in the tumor-draining lymph nodes.
  • Gemcitabine did not increase activation markers on tumor dendritic cells. MHC class II was slightly decreased, and uptake of beads in the tumor was not affected.
• The authors' conclusion: The authors concluded that their data support a model in which gemcitabine chemotherapy increases cross-presentation of tumor antigens by dendritic cells inside the tumor, arming tumor-infiltrating CD8+ T cells. They suggested this could be used in cancer immunotherapy.
• Limitations the authors state:
  • The authors stated that where the cross-presentation block occurs, and which molecular events cause it, remain to be determined by future studies.
  • The authors stated that judging the role of re-stimulation by tumor dendritic cells would require depleting dendritic cells in the tumor at specific times, which this study did not do.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Tumor Microenvironment, Mesothelioma, Gemcitabine, Immunotherapy.

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