Projects

Characterization of the tumor immune architecture

Accumulating evidence indicates that the tumor immune contexture comprising the spatial organization, density, and functional orientation of tumor-infiltrating immune cells plays a critical role for the clinical outcome of cancer patients (Nat Med. 2018;24:541-550; Nat Rev Cancer 2020;20:662–680). Thus, higher frequencies of CD45RO⁺ T helper 1 cells and CD8⁺ T cells were associated with prolonged survival of cancer patients (Science 2006;313:1960-64; Nat Rev Clin Oncol. 2017;14:717-34). When exploring the prognostic value of tumor-infiltrating T cell numbers in colon cancer patients, it has been shown that patients with a so-called high Immunoscore, which is characterized by a high frequency of CD3⁺ and CD8⁺ T cells in the tumor center and the invasive margin, display the longest survival and the lowest risk of recurrence. In addition, it has been reported that higher densities of tumor-infiltrating CD8⁺ T cells at baseline correlate with an improved clinical efficacy of immune checkpoint inhibitor therapy (Nature 2014;515:568-71).

In this context, we investigate the frequency, functional properties, and spatial distribution of immune and stromal cells to gain further insight into the tumor-immune cell crosstalk and the role of distinct immune cell subsets in predicting the treatment response of cancer patients. Multiplexed immunohistochemistry allows for an in-depth characterization of immune cells, while preserving the spatial context of the tumor to further analyze spatial relationships between immune cells and tumor cells. So far, we found that neoadjuvant radiochemotherapy significantly increases the frequency of plasmacytoid dendritic cells (pDCs) in tissues of rectal cancer patients (Front Immunol. 2019;10:602). We also demonstrated that PD-1 expression by lymph node- and tumor-infiltrating regulatory T cells is associated with lymph node metastasis (Cancers. 2020;12:2756) and that tumor-infiltrating T cells expressing LAG3 are associated with reduced disease-free survival in pancreatic cancer  (Cancers. 2021;13:1297). In addition, we showed that a higher frequency of tumor-infiltrating pDCs is significantly correlated with increased survival of colon cancer patients (J Immunother Cancer. 2021;9:e001813). Furthermore, a higher densitiy of whole tumor area- and tumor stroma-infiltrating conventional DCs type 1 and of intraepithelial tumor-infiltrating conventional DCs type 2 was significantly associated with improved survival in pancreatic cancer (Cancers. 2022;14:1216). Moreover, we contributed to a study demonstrating that AXL inhibition in macrophages stimulates antileukemic immunity and elicits effective natural killer cell- and T cell-dependent immune responses against naïve and treatment-resistant leukemia (Cancer Discov. 2021;11:2924-43). Currently, we aim to dissolve the immune contexture of different solid tumors as well as hematological malignancies like leukemia and its modulation by various treatment modalities by analyzing murine and human tumor tissues.

Modulation of the immunostimulatory properties of native human dendritic cells by tumor cells

Dendritic cells (DCs) are professional antigen-presenting cells, which display a unique capacity to induce and expand tumor-reactive CD8⁺ cytotoxic T cells (CTLs) and CD4⁺ T helper cells. CD8⁺ CTLs efficiently destroy tumor cells, whereas CD4⁺ T cells promote the antigen-presenting capacity of DCs and provide help for the stimulation and expansion of tumor-reactive CD8⁺ CTLs. In addition, DCs markedly improve the immunomodulatory and cytotoxic potential of natural killer (NK) cells, which essentially contribute to the elimination of tumor cells. In this context, we investigate the antitumor effects mediated by 6-sulfo LacNAc (slan) DCs (formerly termed M-DC8⁺ DCs), which represent a subpopulation of human blood DCs. In previous studies, it has been demonstrated that activated slanDCs produce large amounts of the cytotoxic effector molecule tumor necrosis factor-a and the immunomodulatory cytokine interleukin-12 (Schäkel et al., Immunity. 2002;17:289-301, Schäkel et al., Immunity. 2006;24:767-777). Functional data revealed that slanDCs efficiently induce antigen-specific CD4⁺ T cells and tumor-reactive CD8⁺ CTLs (Schäkel et al., Eur J Immunol. 1998;28:4084-4093, Schäkel et al., Immunity. 2002;17:289-301). SlanDCs also exhibit direct antibody-dependent and -independent tumor cell lysis (Schmitz et al., Blood. 2002;100:1502-1504, Schmitz et al., J Immunol. 2005;174:4127-4134). Furthermore, they enhance interferon-g secretion and tumor-directed cytotoxicity of NK cells (Schmitz et al., J Immunol. 2005;174:4127-4134, Wehner et al., Int J Cancer. 2009;124:358-366). Currently, we explore whether tumor cells modulate these immunostimulatory properties of slanDCs. In this context, we analyze the ability of tumor cells to influence the maturation and cytokine production of slanDCs. Furthermore, we determine whether tumor cells modulate the capacity of slanDCs to activate NK cells, CD4⁺ T cells and CD8⁺ CTLs.  

Phenotype and functional properties of native human dendritic cells in solid tumors

Infiltrating immune cells are an essential component of the tumor microenvironment of various solid tumors. In this context, recent findings revealed that the frequency and properties of different tumor-infiltrating immune cell subsets can profoundly influence tumor growth. In contrast to tumor-infiltrating T cells, little is known about the phenotype and functional characteristics of native human dendritic cells (DCs) in solid tumors and their impact on clinical outcome. Recently, it has been demonstrated that 6-sulfo LacNAc (slan) DCs accumulate in metastatic tumor-draining lymph nodes from carcinoma patients (Vermi et al., Nat Commun. 2014;5:3029). Following this finding, we investigated the frequency and clinical relevance of infiltrating slanDCs in clear cell renal cell carcinoma. We found that an accumulation of slanDCs in clear cell renal cell carcinoma is associated with a reduced progression-free and overall survival of patients (Toma et al., Oncoimmunology. 2015;4:e1008342). Currently, we explore the phenotype and functional properties of slanDCs and other human native DC subsets in additional solid tumors and the correlation between DC frequency and relevant clinical parameters. These studies may give novel insights into the characteristics of tumor-infiltrating DCs and their impact on the prognosis of tumor patients. In addition, they may have implications for the design of therapeutic strategies that harness tumor-directed functional properties of DCs against tumors.     

Identification of tumor-associated antigens for specific immunotherapy of tumors

Specific immunotherapy represents a promising treatment modality for tumor patients. An interesting immunotherapeutic strategy is based on the stimulation of T cells as potent effectors in antitumor immunity. Current immunotherapeutic strategies comprise the in vivo-induction and -expansion of tumor-reactive T cells by tumor-associated antigen (TAA)-loaded dendritic cells (DCs) and the adoptive transfer of in vitro-generated T cells into tumor patients. Another promising approach is based on the administration of antibodies. The effector mechanisms mediated by monoclonal antibodies include antibody-dependent cellular cytotoxicity, complement activation, and the functional interference of biological pathways essential for tumor growth. Furthermore, recombinant bispecific antibody derivatives directed against a tumor cell surface antigen and an activating receptor on immune effector cells can engage these cells into tumor eradication. In this context, we focuse on the identification of TAAs and derived peptide motifs that can serve as target structures for non-modified or T-cell receptor-engineered T cells. (Schmitz et al., Cancer Res. 2000;60:4845-4849, Kiessling et al., Br J Cancer. 2004;90:1034-1040, Schmitz et al., Br J Cancer. 2007;96:1293-1301). In addition, we define TAAs, which are expressed on the tumor cell surface and represent attractive targets for antibodies and chimeric antigen receptor-engineered T cells (Kiessling et al., Int J Cancer. 2002;102:390-397).