Although the coronavirus disease 2019 (COVID-19) pandemic was declared to be no longer “a public health emergency of international concern” with its wide range of clinical manifestations and late complications, severe acute respiratory syndrome coronavirus 2 infection proved to be a serious threat, especially to the elderly and patients with comorbidities. Patients with oncologic diseases are vulnerable to severe infection and death. Indeed, patients with oncohematological diseases have a higher risk of severe COVID-19 and impaired post-vaccination immunity. Unfortunately, cancer patients are usually excluded from vaccine trials and investigations of post-vaccinal immune responses and the effectiveness of the vaccines. We aimed to elucidate to what extent patients with cancer are at increased risk of developing severe COVID-19 and what is their overall case fatality rate. We also present the current concept and evidence on the effectiveness and safety of COVID-19 vaccines, including boosters, in oncology patients. In conclusion, despite the considerably higher mortality in the cancer patient group than the general population, countries with high vaccination rates have demonstrated trends toward improved survival of cancer patients early and late in the pandemic.

• COVID-19
• COVID-19 vaccines
• RNA vaccines
• Cancer
• Oncological
• Safety
• Efficacy
• Immunogenicity

Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with many studies proving inconclusive or of no benefit in a clinical trial setting. In this review, we highlight the known and unknown about this rare but powerful immune cell. As technologies have expanded our understanding of the complexity of DC development, subsets and response features, we are now left to apply this knowledge to the design of new therapeutic strategies in cancer. We propose that utilization of these technologies through a multiomics approach will allow for an improved directed targeting of DCs in a clinical trial setting. In addition, the DC research community should consider a consensus on subset nomenclature to distinguish new subsets from functional or phenotypic changes in response to their environment.

BACKGROUND: Sentinel lymph nodes (SLNs) are both the first site where breast cancer (BC) metastases form and where anti-tumoral immunity develops. Despite being the most potent antigen-presenting cells, dendritic cells (DCs) located in a nodal tissue can both promote or suppress immune response against cancer in SLNs. METHODS: In SLNs excisions obtained from 123 invasive BC patients, we performed immunohistochemistry (IHC) for CD1a, CD1c, DC-LAMP, and DC-SIGN to identify different DCs populations. Then we investigated the numbers of DCs subsets in tumor-free, micrometastatic, and macrometastatic SLNs with the use of a light microscope. RESULTS: We observed that CD1c+ and DC-SIGN+ DCs were more numerous in SLNs with a larger tumor size. More abundant intratumoral DC-LAMP+ population was related to a higher number of metastatic lymph nodes. Conversely, more abundant CD1a+ DCs were associated with a decreasing nodal burden in SLNs and a lower number of involved lymph nodes. Moreover, densities of the investigated DC populations differed with respect to tumor grade, HER2 overexpression, hormone receptor status, and histologic type of BC. CONCLUSIONS: According to their subtype, DCs are associated with either lower or higher nodal burden in SLNs from invasive BC patients. These relationships appear to be dependent not only on the maturation state of DCs but also on the histological and biological characteristics of the tumor.

• biomarker
• dendritic cells
• immune checkpoint blockade
• immune monitoring
• lung cancer
• prognosis

Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to evade anti-tumor immune responses. To explore the possible involvement of this mechanism in promoting systemic immunosuppression, the pre-treatment levels of soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed breast cancer patients and compared with those of 45 healthy controls using multiplex bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2, whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those of the growth factors, M-CSF, FGF-21 and GDF-15 were significantly increased. However, when analyzed according to the patients’ breast cancer characteristics, these being triple negative breast cancer (TNBC) vs. non-TNBC, tumor size, stage, nodal status and age, no significant differences were detected between the plasma levels of the various immune checkpoint molecules, cytokines, chemokines and growth factors. Additionally, none of these biomarkers correlated with pathological complete response. This study has identified low plasma levels of soluble co-stimulatory and co-inhibitory immune checkpoint molecules in newly diagnosed, non-metastatic breast cancer patients compared to healthy controls, which is a novel finding seemingly consistent with a state of systemic immune dysregulation. Plausible mechanisms include an association with elevated levels of M-CSF and CCL5, implicating the involvement of immune suppressor cells of the M2-macrophage/monocyte phenotype as possible drivers of this state of systemic immune quiescence/dysregulation.

• CD28
• CTLA-4
• GITR
• PD-1/PD-L1
• TIM-3
• breast cancer
• co-inhibitory and co-stimulatory immune checkpoints
• immune dysregulation

The tumor immune contexture plays a pivotal role for the clinical outcome of cancer patients and the efficacy of various treatment modalities. Dendritic cells (DCs) represent a major component of the tumor immune architecture that can either efficiently promote antitumor immunity or contribute to immunosuppression. Here, we investigated the frequency, spatial organization, and clinical significance of tumor-infiltrating conventional DCs type 1 (cDC1s) and type 2 (cDC2s) and plasmacytoid DCs (pDCs) in pancreatic ductal adenocarcinoma (PDAC). A higher frequency of whole tumor area (WTA)- and tumor stroma (TS)-infiltrating cDC1s, and of intraepithelial tumor-infiltrating cDC2s, was significantly associated with improved survival. Furthermore, a higher density of both WTA- and TS-infiltrating cDC1s and pDCs emerged as an independent prognostic factor for better survival. These results provide evidence that tumor-infiltrating DCs are associated with survival of PDAC patients and may support the design of novel DC-based immunotherapeutic strategies.

Dendritic cells (DCs) play a key role in the orchestration of antitumor immunity. Activated DCs efficiently enhance antitumor effects mediated by natural killer cells and T lymphocytes. Conversely, tolerogenic DCs essentially contribute to an immunosuppressive tumor microenvironment. Thus, DCs can profoundly influence tumor progression and clinical outcome of tumor patients. To gain novel insights into the role of human DCs in pancreatic ductal adenocarcinoma (PDAC), we explored the frequency, spatial organization, and clinical significance of conventional DCs type 1 (cDC1s) and type 2 (cDC2s) and plasmacytoid DCs (pDCs) in primary PDAC tissues. A higher density of whole tumor area (WTA)- and tumor stroma (TS)-infiltrating cDC1s was significantly associated with better disease-free survival (DFS). In addition, an increased frequency of intraepithelial tumor-infiltrating cDC2s was linked to better DFS and overall survival (OS). Furthermore, an increased density of WTA- and TS-infiltrating pDCs tended to improve DFS. Moreover, a higher frequency of WTA- and TS-infiltrating cDC1s and pDCs emerged as an independent prognostic factor for better DFS and OS. These findings indicate that tumor-infiltrating DCs can significantly influence the clinical outcome of PDAC patients and may contribute to the design of novel treatment options that target PDAC-infiltrating DCs.

• dendritic cells
• neoadjuvant chemotherapy
• pancreatic cancer
• tumor microenvironment

Advanced non-small cell lung cancer (NSCLC) leads to a high death rate in patients and is a major threat to human health. NSCLC induces an immune suppressive microenvironment and escapes from immune surveillance in vivo. At present, the molecular mechanisms of NSCLC immunopathogenesis and the immune suppressive microenvironment induced by NSCLC have not been fully elucidated. Here, we focus on the effect of NSCLC cells on the development and differentiation of human CD1c⁺ conventional dendritic cell (DC) subsets mediated by CD205 and CD103. The peripheral blood mononuclear cells (PBMCs) were isolated from NSCLC patients and healthy donors. DCs were induced and cocultured with primary NSCLC cells or tumor cell line H1299. DCs without incubation with tumor cells are control. The protein expression of costimulatory molecules such as CD80 and CD86, HLA-DR, pro-/anti-inflammatory cytokines such as IL-10 and IL-12, and CD205 and CD103 on CD1c⁺ DCs was detected by flow cytometry. Our data revealed two new subpopulations of human CD1c⁺ DCs (CD1c⁺CD205⁺CD103⁺ and CD1c⁺CD205⁺CD103⁻ DC) in healthy donors and NSCLC patients. NSCLC cells modulate the development of the CD1c⁺CD205⁺CD103⁺ DC and CD1c⁺CD205⁺CD103⁻ DC subpopulations in vitro and ex vivo. NSCLC cells also suppress the expression of signal molecules such as CD40, CD80, CD86, and HLA-DR on CD1c⁺ DCs. In addition, the production of pro-inflammatory cytokines, including IL-12 and IL-23, is downregulated by NSCLC cells; however, the secretion of anti-inflammatory cytokines, such as IL-10 and IL-27, by CD1c⁺ DCs is upregulated by NSCLC cells. Our results suggest that NSCLC cells may induce immune tolerogenic DCs, which block DC-mediated anti-tumor immunity in NSCLC patients. Our data may be helpful in revealing new cellular mechanisms related to the induction of tolerogenic CD1c⁺ DCs by NSCLCs and the development of an immune suppressive microenvironment that causes tumor cells to escape immune surveillance. Our results indicate a potential role for CD1c⁺ DC subsets mediated by CD205 and CD103 in DC-mediated immunotherapy to target NSCLC in the future.

• CD1c+ cDCs
• dendritic cell
• immune tolerance
• immunotherapy
• non-small lung cancer

• RNA-seq
• cytometry
• dendritic cells
• immune signatures
• prognosis
• single cell RNA-seq

• fellowship European Society for Medical Oncology
• 4th year PhD Fondation ARC pour la Recherche sur le Cancer
• CRCL Institut National de la Santé et de la Recherche Médicale
• PLBIO INCa_4508 Institut National Du Cancer
• Auvergne-Rhône-Alpes Ligue Contre le Cancer
• Saone et Loire Ligue Contre le Cancer
• Comité de Savoie Ligue Contre le Cancer
• LYRICAN, grant no. INCa_4664 SIRIC project
• ANR-10-LABX-0061 LABEX DEVweCAN