C A N C E R

Macrophages limit chemotherapyA major hurdle to successful cancer treatment is tumour resistance to chemotherapy. White blood cells called macrophages often infiltrate tumours in large numbers, and now appear to promote tumour chemoresistance.

M I C H E L E D E P A L M A & C L A I R E E . L E W I S

Malignant tumours are rich in immune cells, including macrophages and neutrophils1. It was initially thought

that the body recruits such cells to tumours in order to defend itself against the developing cancer. However, there is increasing evidence for the opposite being true. For instance, the tumour microenvironment seems to sup-press the normal anticancer functions of both macro phages and another type of immune cell, the cytotoxic T lymphocyte2,3. Even worse, macrophages promote, rather than restrict, tumour progression by stimulating tumour vascularization, invasion and meta-stasis3. Now, in a fascinating paper published in Cancer Discovery, DeNardo et al.4 show that these cells can also enhance tumour resistance to chemotherapy.

Macrophages and neutrophils are normally at the front line of the body’s defence: they engulf pathogens and dead or dying cells, and repair wounds. These white blood cells (leukocytes) also function in tumours, along with cells that determine the specificity of the immune response against foreign agents — T and B lymphocytes. Previous work by the same team4 showed that subpopulations of leukocytes, including macrophages, com-municate with one another in tumours to pro-mote malignancy. In mouse models of cancer, for example, the CD4+ helper T lymphocytes and B lymphocytes release interleukin-4 (an immune mediator) and antibodies, respec-tively, to stimulate the tumour-promoting functions of macrophages5,6.

The first hint that the function of these tumour-associated macrophages (TAMs) and lymphocytes might be linked in human tumours comes from the present study4. DeNardo et al. identified a distinct immune-cell ‘signature’ in surgically removed breast tumours that predicted the survival of patients: women with a combination of high TAMs, high CD4+ helper T cells and low cytotoxic T cells in their tumours were at high risk of developing secondary tumours and, therefore, of succumbing to the disease. Earlier studies had established a link between poor prognosis and either high TAM numbers3,7 or low T-cell numbers8 in tumours. What DeNardo et al.

show for the first time is the pronounced prog-nostic value of the inverse correlation between numbers of TAMs and cytotoxic T cells.

The researchers4 also show that breast tumours with high TAM numbers and low numbers of cytotoxic T cells respond relatively poorly to chemotherapy given before surgery. This may be because chemotherapy stimulates tumour cells to release a protein called CSF1. Indeed, in mouse mammary tumours, chemo-therapy increased tumour-cell expression of CSF1, which then recruited large numbers of macrophages expressing the CSF1 recep-tor to the tumour. This effect may depend on the chemotherapeutic agent used, the type of tumour, and even the immune status of the host. For example, in a previous study9, a different form of chemotherapy failed to increase TAM numbers in human breast tumours grown in mice lacking T cells.

Pharmacological blockade of macrophage

Figure 1 | Macrophages promote tumour chemoresistance. Progressing mammary tumours contain a variety of leukocytes, including tumour-associated macrophages (TAMs) and cytotoxic T cells. DeNardo et al.4 report that TAM depletion in such tumours increased the antitumour efficacy of the chemotherapeutic agent paclitaxel. Consequently, paclitaxel treatment resulted in a greater reduction in tumour size in TAM-depleted tumours, which also contained fewer blood vessels, higher numbers of cytotoxic T cells and more signs of tumour destruction. It also reduces the extent of metastasis in organs such as the lung.

recruitment markedly improved the ability of the chemotherapeutic agent paclitaxel to slow the growth of both primary and metastatic tumours (Fig. 1). DeNardo and colleagues sug-gest that the ability of TAMs to limit tumour responses to chemotherapy is, at least in part, due to their suppression of the antitumour functions of cytotoxic T cells. Their paper

therefore attests to the functional complex-ity of the immune-cell repertoire in tumours and shows that crosstalk between TAMs and cytotoxic T cells affects tumour responses to chemotherapy. Nonetheless, more work is required to better dissect this phenomenon and its therapeutic relevance.

TAMs themselves represent a heterogene-ous assortment of functionally distinct cells3. Recent studies3,10 in mice have identified and characterized various TAM subsets by their gene-expression signatures and specific loca-tion in distinct tumour regions. Furthermore, genetic tools have helped to elucidate specific functions of these TAM subsets3,10,11.

Intriguingly, DeNardo et al. report that blocking CSF1 receptors selectively inhibits TAM infiltration into tumour regions distant from the blood vessels, leaving perivascular TAMs apparently unaffected. Because this partial depletion of TAMs improved the effi-cacy of chemotherapy, it is conceivable that the TAMs present in poorly vascularized areas specifically protect tumours from the effects of chemotherapy. Further studies are warranted to characterize this subset of TAMs and to see whether their exposure to distinct signals in

Paclitaxel

TAMdepletion

Progressing tumour Chemoresponsive tumour

↑ Metastasis ↓ Metastasis

TAM

PerivascularTAM

Cytotoxic T cell

Bloodvessel

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50 Years AgoIn Nature of October 12, 1957 … we were glad and proud to congratulate the scientists and technologists of the U.S.S.R. on the successful launching of the first artificial Earth satellite (Sputnik I). Less than a month afterwards … we again had occasion to congratulate the U.S.S.R., when the second satellite (Sputnik II) was launched, this time containing a dog ... Now again, on April 12, a still further point in scientific advancement was reached, for on that day scientists and technologists in the U.S.S.R. reaped a rich reward for concentrated and ingenious research by successfully launching another space-vehicle (Vostok) into space. This satellite carried, among other things, a man (Major Yuri Alekseyevich Gagarin), travelled in orbit around the Earth in 89 min. 6  sec., and a little later was brought back safely to Earth, with Major Gagarin unharmed — all in about 108 min.From Nature 22 April 1961

100 Years AgoThe first non-stop flight from London to Paris was made, on April 12, on a Blériot monoplane by M. Pierre Prier in 3h. 56m. M. Prier, who is the chief instructor of the Blériot School at Hendon, left that ground at 1.37 p.m., taking a course for Dover via Hampstead, Highgate, Greenwich, Chatham, and Canterbury … [H]e reached Dover, at 2.50 p.m. Thirty minutes later he was over Boulogne, and steering a straight course over Abbeville and Beauvais for Paris, where he arrived at 5.33 p.m., making a perfect landing in front of the Blériot sheds at the Issy-les-Moulineaux aviation ground … M. Prier … suffered no inconvenience throughout the journey except slight inflammation of the eyes, due to his neglecting to equip himself with goggles.From Nature 20 April 1911

E L E C T R O N I C S

Power surfing on wavesWavy strips of piezoelectric materials on stretchable substrates can both withstand larger applied mechanical strain without cracking and harvest energy more efficiently than their flat counterparts.

M I N H Y U N G L E E & A L I J A V E Y

Bendable and stretchable electronics such as roll-up keyboards and displays have garnered tremendous attention because

of their portability and versatility. However, a major limitation of all portable devices availa-ble today is their short battery life, which often limits their functional use to just a few hours after a full charge. If an electronic device could be self-powered — for instance, by harvesting energy from the mechanical deformation it undergoes during typing, rolling and unrolling — then the power problem would be greatly reduced. Writing in Nano Letters, Qi et al.1 describe a technique to produce thin ribbons of wavy piezoelectric materials on rubber sub-strates that paves the way to the realization of highly stretchable, energy-harvesting devices.

In piezoelectric materials, applied

mechanical strain results in the accumulation of electric charge and the generation of electric-ity. This phenomenon, known technically as the piezoelectric effect, was first observed in 1880 by the French physicists and brothers Pierre and Jacques Curie. Since then, the effect has been used in a wide range of applications, includ-ing sensors and energy-harvesting devices. A few popular examples of inorganic piezoelec-tric materials include zinc oxide, aluminium nitride and lead zirconate titanate (PZT).

In their bulk form, these inorganic semi-conductors are mechanically rigid. But once miniaturized to strips or wires of nanometre- scale thickness, they become mechanically flexible. Stretchability, however, is more challenging. In the past, researchers have demonstrated2 that buckled silicon ribbons with periodic, wavy (sinusoidal) shapes can accommodate extreme increases in maximum

these tumour sites stimulates their chemo-protective functions. It will then be possible to investigate whether a similar TAM subset exists in human breast tumours — and in other types of tumour.

The authors also found that the combina-tion of TAM depletion and chemotherapy reduced tumour-vessel density by 50% and led to greater tumour destruction. TAMs are known to stimulate excessive tumour vascu-larization3,7,10,12, and their persistent expres-sion of pro-angiogenic factors such as VEGF induces the formation of abnormal, hypo-per-fused blood vessels, which limit the delivery of chemotherapy to tumours10,11. It is therefore conceivable that TAM depletion at sites away from blood vessels4 may have skewed the peri-vascular TAMs from a pro-angiogenic3,10 to an angiostatic function12, thereby ‘normalizing’ the remaining vessels to acquire the structure and function of vessels in healthy tissues. This would temporarily increase blood flow to the tumour, enhancing the delivery and so the efficacy of the chemotherapeutic agent.

The findings of DeNardo and colleagues4 add weight to an emerging compelling case for deci-phering the complexity of leukocyte infiltrates in breast cancer. Their findings suggest that this may provide clinically relevant indications of the likely response to chemotherapy and thus patient survival. Future studies should show the relevance of the chemoprotective subset of TAMs that these authors identify for human

cancer, and may even highlight molecular tar-gets for therapies that restrain the activity of these cells or even reactivate their antitumour functions. Such reprogramming of the immune microenvironment in tumours is a promising strategy for improving the efficacy of standard anticancer treatments. ■

Michele De Palma is at the Angiogenesis and Tumour Targeting Research Unit, and HSR-TIGET, San Raffaele Scientific Institute, 20132-Milan, Italy. Claire E. Lewis is at the

Academic Unit of Tumour Inflammation & Tumour Targeting, Department of Oncology, University of Sheffield Medical School, Sheffield S10 2RX, UK. e-mails: depalma.michele@hsr.it; claire.lewis@sheffield.ac.uk

1. de Visser, K. E., Eichten, A., Coussens, L. M. Nature Rev. Cancer 6, 24–37 (2006).

2. Mellor, A. L. & Munn, D. H. Nature Rev. Immunol. 8, 74–80 (2008).

3. Lewis, C. E. & Pollard, J. W. Cancer Res. 66, 605–612 (2006).

4. DeNardo, D. G. et al. Cancer Discov. doi:10.1158/2159-8274.CD-10-0028 (2011).

5. DeNardo, D. G., Andreu, P. & Coussens, L. M. Cancer Metastasis Rev. 29, 309–316 (2010).

6. Andreu, P. et al. Cancer Cell 17, 121–134 (2010). 7. Bingle, L., Brown, N. J. & Lewis, C. E. J. Pathol. 196,

254–265 (2002).8. Galon, J. et al. Science 313, 1960–1964 (2006).9. Paulus, P., Stanley, E. R., Schäfer, R., Abraham, D. &

Aharinejad, S. Cancer Res. 66, 4349–4356 (2006).10. Pucci, F. et al. Blood 114, 901–914 (2009).11. Stockmann, C. et al. Nature 456, 814–818 (2008).12. Rolny, C. et al. Cancer Cell 19, 31–44 (2011).

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