Cancer: Macrophages limit chemotherapy
Michele De Palma & Claire E. Lewis
Nature 472, 303–304 (21 April 2011) doi:10.1038/472303a
Published online 20 April 2011
A 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.
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 suppress the normal anticancer functions of both macrophages 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 metastasis3. 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, communicate with one another in tumours to promote malignancy. In mouse models of cancer, for example, the CD4+ helper T lymphocytes and B lymphocytes release interleukin-4 (an immune mediator) and antibodies, respectively, 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 prognostic 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, chemotherapy increased tumour-cell expression of CSF1, which then recruited large numbers of macrophages expressing the CSF1 receptor 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 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 suggest 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 complexity 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.
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.
Full size image (101 KB)
TAMs themselves represent a heterogeneous assortment of functionally distinct cells3. Recent studies3, 10 in mice have identified and characterized various TAM subsets by their gene-expression signatures and specific location 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 efficacy 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 these tumour sites stimulates their chemoprotective 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 combination of TAM depletion and chemotherapy reduced tumour-vessel density by 50% and led to greater tumour destruction. TAMs are known to stimulate excessive tumour vascularization3, 7, 10, 12, and their persistent expression of pro-angiogenic factors such as VEGF induces the formation of abnormal, hypo-perfused 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 perivascular 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 deciphering 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 targets 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.