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Abstract
Abundant macrophage infiltration of solid cancers commonly correlates with poor prognosis. Tumor-promoting functions of macrophages include angiogenesis, metastasis formation, and suppression of Th1-type immune responses. Here, we show that successful treatment of cervical carcinoma in mouse models with synthetic long peptide (SLP) vaccines induced influx of cytokine-producing CD8 T cells that strongly altered the numbers and phenotype of intratumoral macrophages. On the basis of the expression of CD11b, CD11c, F4/80, Ly6C, Ly6G, and MHC II, we identified four myeloid subpopulations that increased in numbers from 2.0-fold to 8.7-fold in regressing tumors. These changes of the intratumoral myeloid composition coincided with macrophage recruitment by chemokines, including CCL2 and CCL5, and were completely dependent on a vaccine-induced influx of tumor-specific CD8 T cells. CD4 T cells were dispensable. Incubation of tumor cells with T cell-derived IFNγ and TNFα recapitulated the chemokine profile observed in vivo, confirming the capacity of antitumor CD8 T cells to mediate macrophage infiltration of tumors. Strikingly, complete regressions of large established tumors depended on the tumor-infiltrating macrophages that were induced by this immunotherapy, because a small-molecule drug inhibitor targeting CSF-1R diminished the number of intratumoral macrophages and abrogated the complete remissions. Survival rates after therapeutic SLP vaccination deteriorated in the presence of CSF-1R blockers. Together, these results show that therapeutic peptide vaccination could induce cytokine-producing T cells with strong macrophage-skewing capacity necessary for tumor shrinkage, and suggest that the development of macrophage-polarizing, rather than macrophage-depleting, agents is warranted.
Highlights
Cervical cancer is strongly associated with human papillomavirus (HPV) infection (1, 2)
Established TC-1 mouse tumors, which are transformed by the E6 and E7 oncogenes of HPV16, respond to prophylactic and therapeutic vaccination with an synthetic long overlapping peptides (SLP), comprising the immunodominant E7 peptide emulsified in the mineral oil–based adjuvant Incomplete Freunds Adjuvant (IFA)
This conclusion was confirmed by our observation that CD4 depletion had no effect on vaccine-induced changes (Fig. 1G) and that mice that were injected with an empty IFA depot had a comparable myeloid cell tumor infiltration as untreated tumors (Supplementary Fig. S1A)
Summary
Cervical cancer is strongly associated with human papillomavirus (HPV) infection (1, 2). The two HPV oncogenes E6 and E7 are critical for maintenance of cellular transformation; they are constitutively expressed by HPV-associated tumors and are ideal targets for therapeutic vaccination (3). We have shown that overlapping synthetic long overlapping peptides (SLP) comprising these proteins are capable of inducing potent T-cell responses in mice and humans (4–7). In patients with premalignant lesions, vaccine-induced T-cell responses correlate with complete clinical responses. In patients with advanced or recurrent HPV16induced gynecologic carcinoma, there is no apparent effect on. Note: *S.H. van der Burg and T. van Hall share last authorship
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