Evading immune destruction and tumor promoting inflammation are important hallmarks in the development of cancer. Macrophages are present in most human tumors and are often associated with bad prognosis. Tumor associated macrophages come in many functional flavors ranging from what is known as classically activated macrophages (M1) associated with acute inflammation and T-cell immunity to immune suppressive macrophages (M2) associated with the promotion of tumor growth. The role of these functionally different myeloid cells is extensively studied in mice tumor models but dissimilarities in markers and receptors make the direct translation to human cancer difficult. This review focuses on recent reports discriminating the type of infiltrating macrophages in human tumors and the environmental cues present that steer their differentiation. Finally, immunotherapeutic approaches to interfere in this process are discussed.

In a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16⁺)–induced or HPV18⁺-induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4⁺, CD8⁺, and regulatory T cells as well as by calculation of the ratio of CD8⁺/CD4⁺ T cells and CD8⁺/regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6- and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN⁻) or presence (LN⁺) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8⁺ T-cell tumor infiltration, a higher CD8⁺/CD4⁺ T-cell ratio, and higher CD8⁺/regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR⁺) or absence (IR⁻) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8⁺ T cells was found in the group of LN⁻ patients displaying a concomitant systemic tumor-specific immune response (LN⁻IR⁺). CD8⁺ T-cell infiltration in LN⁻IR⁻ patients was comparable with that of LN⁺ patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN⁻ patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis. [Cancer Res 2007;67(1):354–61]

The success of checkpoint blockade therapy revolutionized cancer treatment. However, we need to increase the fraction of responding patients and overcome acquired resistance to these therapies. Recently, the inhibitory receptor NKG2A received attention as a new kid on the block of immune checkpoints. This receptor is selectively expressed on cytotoxic lymphocytes, including natural killer cells and CD8 T cells, and NKG2A+ T cells are preferentially residing in tissues, like the tumor microenvironment. Its ligand, histocompatibility leucocyte antigen E (HLA-E), is a conserved nonclassical HLA class I molecule that binds a limited peptide repertoire and its expression is commonly detected in human cancer. NKG2A blockade as a standalone therapy appears poorly effective in mouse tumor models, however, in the presence of activated T cells, for example, induced by PD-1/PD-L1 blockade or cancer vaccines, exerts strongly enhanced efficacy. Clinical trials demonstrated safety of the humanized NKG2A-blocking antibody, monalizumab, and first results of phase II trials demonstrate encouraging durable response rates. Further development of this axis is clearly warranted.

Purpose: The interaction between programmed cell death 1 (PD-1), expressed by activated effector or regulatory T cells, and B7-H1 (PD-L1) and B7-DC (PD-L2) results in the inhibition of T-cell function. The aim of this study was to determine B7-H1, B7-DC, and PD-1 expression in cervical carcinoma.

Anti‐tumor vaccines consisting of extended CTL peptides in combination with CpG‐ODN were shown to be superior to those comprising minimal CTL epitopes and CpG‐ODN, in that they elicit stronger effector CTL responses with greater tumoricidal potential. We now demonstrate that this improved performance is primarily due to the focusing of CTL epitope presentation onto activated DC in the inflamed lymph nodes draining the vaccination site. In the case of vaccination with minimal peptides, additional APC including T and B cells are also loaded with CTL epitopes. Our data suggest that circulation of these peptide‐loaded lymphocytes leads to epitope presentation in non‐inflamed lymphoid organs distal from the vaccination site, in the absence of potent costimulatory signals required for efficient CTL priming. The resulting blend of pro‐immunogenic and tolerogenic signals, which results in suboptimal activation of the CTL response, is avoided by vaccinating with extended CTL peptides. An additional advantage of extended CTL peptide vaccines is an increased duration of in vivo epitope presentation.

One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFNγ (P= 0.0003) and IL-5 (P< 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific CD4⁺CD25⁺Foxp3⁺T cells (P= 0.005) and displayed a lower HPV16-specific IFNγ/IL-10 ratio after vaccination (P< 0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specific CD4⁺CD25⁺Foxp3⁺T cells was predictive of clinical success. Foxp3⁺T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure.