TAMs arise from inflammatory monocytes but do not resemble alternatively activated M2 macrophages.
Major finding: TAMs arise from inflammatory monocytes but do not resemble alternatively activated M2 macrophages.
Concept: Notch-dependent TAM differentiation leads to accumulation of tumor-infiltrating PD-1+ T cells.
Impact: Understanding of the origin and function of TAMs may guide cancer immunotherapy strategies.
Macrophages have been implicated in cancer progression, but the origin and function of tumor-associated macrophages (TAM) are poorly understood. Utilizing the MMTV-PyMT mammary tumor model, Franklin and colleagues defined a major population of tumor-infiltrating myeloid cells as tumor-associated macrophages (TAM) based on their transcriptional profile. During tumor growth, the population of mammary tissue macrophages (MTM) that normally reside in untransformed mammary glands was reduced, whereas the number of TAMs increased. Depletion of circulating inflammatory monocytes by genetic depletion of C-C chemokine receptor type 2 (Ccr2) led to a reduction of TAMs, indicating that mammary tumor growth induces the differentiation of circulating CCR2-positive inflammatory monocytes into TAMs. Gene expression analysis showed that unlike MTMs, TAMs had increased expression of several integrins and the integrin receptor VCAM1. Moreover, in this context TAMs were also found to be distinct from M2 or alternatively activated macrophages, as TAMs did not express M2 markers and TAM differentiation still occurred in the absence of factors that are necessary for M2 polarization; these findings were surprising given that TAMs have been presumed to have an M2 phenotype. TAMs were found to have increased expression of Notch pathway components, and genetic deletion of the Notch transcription factor gene Rbpj in MMTV-PyMT mice inhibited the terminal differentiation of inflammatory monocytes into TAMs and reduced mammary tumor burden without affecting MTMs. As MMTV-PyMT tumors grew and TAMs expanded, the population of infiltrating T cells expressing the inhibitory receptor programmed death-1 (PD-1) increased, suggesting that TAMs promote tumor growth by suppressing antitumor immune responses. Although characterization of TAMs in additional murine models and human cancers is warranted, these data suggest that TAMs are genetically and functionally distinct from normal macrophages, are derived from circulating inflammatory monocytes, and promote tumor progression via modulation of the cytotoxic T-cell response.
Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, et al. The cellular and molecular origin of tumor-associated macrophages. Science 2014;344:921–5.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.