Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer?

Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent 'cancer immunoediting' has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment

Poly(I:C) Enhances the Susceptibility of Leukemic Cells to NK Cell Cytotoxicity and Phagocytosis by DC

α Active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells

Release of NK cell IFN-γ upon stimulation with poly(I:C)-electroporated U-937 cells.

<p>Concentration of IFN-γ secreted by NK cells in two- and three-party cell cultures. Cocultures were held overnight at a 1∶1 NK:U-937 or a 1∶1∶1 NK:DC:U-937 cell ratio. Horizontal lines represent median values for 7 donors. Differences are statistically significant if p<0.05. Abbreviations: mock EP, electroporated without poly(I:C); pIC EP, electroporated with poly(I:C).</p

Correlations of functional properties of NK cells and DC regarding poly(I:C) electroporation of the U-937 cell line.

<p>(<b>A</b>) Positive correlation between the effect of poly(I:C) electroporation of U-937 cells on the NK cell killing capacity and the DC phagocytic function, expressed as the difference (delta) in functions between mock- and poly(I:C)-electroporated U-937 cells. (<b>B</b>) The concentrations IFN-α and IFN-γ in supernatant of NK cell:U-937 poly(I:C)-electroporated cocultures are strongly correlated. The improved (<b>C</b>) phagocytosis by immature DC and (<b>D</b>) killing by NK cells are in positive relation with the concentration IFN-α secreted by poly(I:C)-electroporated U-937 cells. Spearman rank correlations were calculated for defined functions. Abbreviations: mock EP, electroporated without poly(I:C); pIC EP, electroporated with poly(I:C); Δ killing  =  % killing of poly(I:C)-electroporated tumor cells - % killing of mock-electroporated tumor cells; Δ phagocytosis  =  % phagocytosis of poly(I:C)-electroporated tumor cells - % phagocytosis of mock-electroporated tumor cells.</p

BDCA1+CD14+ Immunosuppressive Cells in Cancer, a Potential Target?

Dendritic cell (DC) vaccines show promising effects in cancer immunotherapy. However, their efficacy is affected by a number of factors, including (1) the quality of the DC vaccine and (2) tumor immune evasion. The recently characterized BDCA1+CD14+ immunosuppressive cells combine both aspects; their presence in DC vaccines may directly hamper vaccine efficacy, whereas, in patients, BDCA1+CD14+ cells may suppress the induced immune response in an antigen-specific manner systemically and at the tumor site. We hypothesize that BDCA1+CD14+ cells are present in a broad spectrum of cancers and demand further investigation to reveal treatment opportunities and/or improvement for DC vaccines. In this review, we summarize the findings on BDCA1+CD14+ cells in solid cancers. In addition, we evaluate the presence of BDCA1+CD14+ cells in leukemic cancers. Preliminary results suggest that the presence of BDCA1+CD14+ cells correlates with clinical features of acute and chronic myeloid leukemia. Future research focusing on the differentiation from monocytes towards BDCA1+CD14+ cells could reveal more about their cell biology and clinical significance. Targeting these cells in cancer patients may improve the outcome of cancer immunotherapy