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Published on: November 28, 2019
HPV16 tumor associated macrophages suppress antitumor T cell responses
Ana Paula Lepique1, Katia Regina Perez Daghastanli, Iolanda Midea Cuccovia
1Laboratory of Virology Ludwig Institute for Cancer Research, São Paulo branch, Rua João Julião, 245, São Paulo, SP, Brazil. alepique@ludwig.org.br
Purpose:
High-risk human papillomavirus (HPV) is the main etiologic factor for cervical cancer. The severity of HPV-associated cervical lesions has been correlated to the number of infiltrating macrophages. The objective of this work is to characterize the role of tumor-associated macrophages (TAM) on the immune cellular response against the tumor.
Experimental Design:
We used the HPV16 E6- and E7-expressing TC-1 mouse tumor model to study the effect of TAM on T-cell function in vitro, and depleted TAM, using clodronate-containing liposomes, to characterize its role in vivo.
Results:
TAM, characterized by the positive expression of CD45, F4/80, and CD11b, formed the major population of infiltrating tumor cells. TAM displayed high basal Arginase I activity, producing interleukin-10 (IL-10); they were resistant to iNOSII activity induction, therefore reversion to M1 phenotype, when stimulated in vitro with lipopolysaccharide/IFNgamma, indicating an M2 phentoype. In cultures of isolated TAM, TAM induced regulatory phenotype, characterized by IL-10 and Foxp3 expression, and inhibited proliferation of CD8 lymphocytes. In vivo, depletion of TAM inhibited tumor growth and stimulated the infiltration of tumors by HPV16 E7(49-57)-specific CD8 lymphocytes, whereas depletion of Gr1(+) tumor-associated cells had no effect.
Conclusions:
M2-like macrophages infiltrate HPV16-associated tumors causing suppression of antitumor T-cell response, thus facilitating tumor growth. Depletion or phenotype alteration of this population should be considered in immunotherapy strategies.
Insights
Tumor-associated macrophages (TAM) with an M2-like phenotype infiltrate human papillomavirus (HPV)-associated tumors, suppressing anti-tumor T-cell responses and promoting tumor growth. Modulating TAM may enhance cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- High-risk human papillomavirus (HPV) is a primary cause of cervical cancer.
- The number of infiltrating macrophages correlates with the severity of HPV-associated cervical lesions.
Purpose of the Study:
- To investigate the role of tumor-associated macrophages (TAM) in the immune response against HPV-induced tumors.
- To characterize TAM's impact on T-cell function and tumor growth.
Main Methods:
- Utilized the TC-1 mouse model, which expresses HPV16 E6 and E7.
- Studied TAM function in vitro and depleted TAM in vivo using clodronate-liposomes.
- Analyzed T-cell responses and tumor growth following TAM depletion.
Main Results:
- TAMs, identified as CD45+, F4/80+, CD11b+, exhibited an M2-like phenotype with high Arginase I and IL-10 production, resisting M1 polarization.
- Isolated TAMs induced regulatory T-cells (IL-10, Foxp3+) and suppressed CD8+ lymphocyte proliferation in vitro.
- In vivo, TAM depletion reduced tumor growth and increased infiltration of HPV16 E7-specific CD8+ T-cells.
Conclusions:
- M2-like TAMs suppress anti-tumor T-cell immunity, facilitating HPV-associated tumor progression.
- Targeting TAMs, through depletion or phenotype modification, represents a potential strategy for enhancing cancer immunotherapy.
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