Helmholtz Zentrum München, Germany
I am trained as cellular immunologist and can document long-standing experience in the analysis of human immune cells from patient blood and tissues. I have been studying the biology of HLA, the antigen presentation for T cell recognition since my PhD thesis and during my postdoctoral training (Noessner & Parham 1995). As research staff and group leader, I was subsequently involved in identifying antigen specificity of human tumor-infiltrating T lymphocytes (Schendel et al. 1997) and pioneering work of TCR cloning. It was shown that TCR gene transfer redirected human T lymphocytes towards recognition of RCC. These early works paved the way for the wider application of adoptive T cell transfer for cancer therapy (Engels et al., 2005; Leisegang et al. 2010). In recent works, I designed chimeric co-signaling proteins to empower adoptive T cell therapies by enhancing activity of engineered T cells in the tumor milieu through spatially organized provision of survival signals and co-stimulation (Schlenker et al. 2017).
Recognizing that T cells with tumor-reactive TCR are cytotoxic ex vivo, but fail to perform tumor eradication in situ, I sought to gain knowledge about the fate and functional state that immunocytes acquire within the tissue milieus. We observed that RCC tissues contained NK cells at varied frequency and that a high frequency correlated with better functional activity and longer patient survival (Schleypen et al. 2006; Eckl et al. 2012). Moreover, we identified unusually polarized myeloid cells in RCC tissue, which we named ercDCs. High numbers of ercDCs were found in tumors with poor prognosis (Figel et al. 2011; Brech et al. 2020). We speculate that ercDCs are involved in tumor immune escape and patients whose tumors harbor high numbers of ercDCs should receive combination therapy of checkpoint inhibition with myeloid cell depletion or repolarization, such as TKIs (Noessner et al. 2012).
T and NK cells in RCC and prostate cancer tissue were found to be depleted of perforin and unable to respond to stimulation (Ebelt et al. 2008; Prinz et al. 2012, 2014). Unresponsiveness could be linked to blunted ERK pathway activation which could be restored by inhibiting diacylglycerol kinase-α (DGK-α). Since DGK-α is active downstream of CTLA-4 and PD-1/PD-L1 checkpoints, DGK-α inhibition should synergize with checkpoint blockade antibodies (Noessner 2017), a hypothesis that is currently tested in vitro.
Among various tumor environmental factors, tumor lactic acidosis was observed to completely block IFN-γ secretion and impair cytotoxicity of cytotoxic T cells (Mendler et al. 2012; Fischbeck et al. 2020). Acid neutralization restored T cell activity in vitro. Collagen density (Kuczek et al. 2019) and PD-L1 (Hänze et al. 2019) are additional factors of the tumor environment that influence T cell infiltration and patient survival.
Collectively, these results indicate that the analysis of the tumor microenvironment and its infiltrating immune cells can help to identify relevant immune escape mechanisms and will help to select the most beneficial immunotherapy.
Disclosure information not submitted.
Saturday, April 23, 2022
11:20 – 11:30 CEST