HighlightsTumor immune escape compromises the efficacy of cancer immunotherapy.Loss of MHC class I expression is a frequent event in cancer cells.Three tumor phenotypes determine cancer fate: escape, rejection and dormancy.Recovery of MHC class I expression is required to improve cancer immunotherapy.

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One of the hallmarks of cancer is the influx of myeloid cells. In our study, we investigated the constitution of tumorinfiltrating myeloid cells and their relationship to other tumor-infiltrating immune cells, tumor characteristics and the diseasespecific survival of patients with cervical cancer (CxCa). Triple-color immunofluorescence confocal microscopy was used to locate, identify and quantify macrophages (CD14), their maturation status (CD33) and their polarization (CD163) in a cohort of 86 patients with cervical carcinoma. Quantification of the numbers of myeloid cells revealed that a strong intraepithelial infiltration of CD141 cells, and more specifically the population of CD141CD332CD1632 matured M1 macrophages, is associated with a large influx of intraepithelial T lymphocytes (p 5 0.008), improved disease-specific survival (p 5 0.007) and forms an independent prognostic factor for survival (p 5 0.033). The intraepithelial CD81 T-cell and regulatory T-cell (Treg) ratio also forms an independent prognostic factor (p 5 0.010) and combination of these two factors reveals a further increased benefit in survival for patients whose tumor displays a dense infiltration with intraepithelial matured M1 macrophages and a high CD8 T-cell/Treg ratio, indicating that both populations of immune cells simultaneously improve survival. Subsequently, we made a heatmap including all known immune parameters for these patients, whereby we were able to identify different immune signatures in CxCa. These results indicate that reinforcement and activation of the intratumoral M1 macrophages may form an attractive immunotherapeutic option in CxCa. Cervical cancer (CxCa) is caused by high-risk human papillomavirus (HPV).1 Studies on HPV-specific T-cell responses in patients with premalignant disease suggest that spontaneous regression occurs when circulating HPV early antigen-specific CD41 and CD81 T-cells are present and when the lesions are infiltrated with effector T-cells that outnumber regulatory Tcells (Tregs). Moreover, the presence of circulating HPVspecific CD41 T-cells is associated with T-cell infiltration in the lesion and favorable clinical outcome in high-grade squamous intraepithelial lesion after treatment.2,3 The development of CxCa is associated with a weak systemic and local immune response to HPV, reflected by low numbers of tumorinfiltrating T-cells comprising CD81 cytotoxic T-cells, CD41 T-helper cells and Tregs. [4][5][6] The T-cells present often lack cytotoxicity 7 and/or express coinhibitory molecules such as programmed cell death protein 1, CD94 and NKG2a. 8,9 Tumors also downregulate human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) and upregulate HLA-E and PD-L1 to further restrain the CD81 T-cell response. 2,[8][9][10] The presence of circulating HPV-specific T-cells associates with better survival and high numbers of T-cells correlate with the absence of metastases or a relapse. 2,6,11,12 Importantly, the ratio between tumor-infiltrating CD81 and Foxp31 T-cells wa...

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