Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions.
Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Marie
M
Lundholm
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Christina
C
Hägglöf
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Maria L
ML
Wikberg
Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
Pär
P
Stattin
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
Lars
L
Egevad
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Anders
A
Bergh
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Pernilla
P
Wikström
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Richard
R
Palmqvist
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Sofia
S
Edin
D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018655:Lymphocyte Count; D008264:Macrophages / Q000145:classification / Q000166:cytology / Q000276:immunology*; D008297:Male; D011379:Prognosis; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D016207:Cytokines