ICML 2025 | The prognostic significance and therapeutic potential of the TLR 7/8 pathway in CNS lymphomas

So this is an area that we are greatly interested in is trying to understand factors that contribute to therapeutic resistance in CNS lymphomas which historically have been associated with a poor prognosis and devastating morbidity because of the activity of the lymphoma to disseminate in the neuroaxis. One of the hypotheses we’re pursuing is that the myeloid microenvironment, both tumor-infiltrating macrophages and microglia, contribute to this resistance. So via a variety of studies, we are dissecting the biology of macrophages in patients, clinical specimens, and in preclinical models to understand key factors that are important for how macrophages may inhibit therapeutic activity and promote lymphomagenesis in the brain. One of the approaches we’ve pursued has been phenotyping the circulating macrophages in the tumor microenvironment of the spinal fluid in the course of clinical investigations. We’ve shown by flow cytometry that we can identify classically activated M1 macrophages, which have the transcriptional signature identical to macrophages programmed or polarized in vitro with interferon gamma. And yet we can also identify selectively in CNS lymphoma patients, if not in their peripheral blood, nor in patients without CNS lymphoma, neurologic controls, a population of M2 macrophages. And we’ve shown in the course of these investigations that the accumulation of M1 macrophages in the spinal fluid in patients serially over time correlates with better outcome in patients receiving rituximab and methotrexate as well as lenalidomide. And that importantly the loss of these M1 macrophages which have antigen presentation machinery as shown by transcriptional profiling, they have positively participated in the immune response. Loss of these macrophages is associated with disease progression. A second line of investigation we’ve been pursuing has been the analysis of macrophages in biologic and diagnostic specimens of CNS lymphoma and here we’ve shown that number one these macrophages tend to have an M1 phenotype that is they express HLA-DR and iNOS CD64 consistent with an interferon gamma signature. And secondly, we’ve shown that their accumulation correlates positively with the accumulation of cytotoxic T cells in diagnostic specimens such that there’s a positive correlation between macrophages, macrophage content in tumors and T-cell content as well as favorable prognosis. And finally, we’ve shown in a variety of preclinical models the importance of interferon gamma using interferon gamma knockout mice as well as pharmacologic administration of interferon gamma in immunocompetent mice. We’ve been able to show that the presence of interferon gamma correlates with delayed tumor progression. Lack of interferon gamma correlates with rapid tumor progression. These models involving both syngeneic as well as patient-derived xenografts. And then phenotypic analysis of these macrophages in these interferon gamma knockout mice led to the determination that toll-like receptors 7 and 8 are likely key drivers of this favorable prognosis associated with the M1 phenotype. And indeed, we’ve demonstrated that by analysis of diagnostic specimens from patients showing that TOLL-like receptor expression by immunohistochemistry as well as by an independent set of cases via transcriptional profiling. In both these datasets, discovery and validation sets, the presence of TLR expression correlated favorably with outcome as well as with CD8 content T-cell transcripts. And finally, we then, in collaboration with a company called Gilead, we’ve been pursuing the testing of the hypothesis that pharmacologic administration of small molecule toll-like receptor agonists, which stimulate through their biological similarity to single-stranded RNA, they activate TLR7 and 8 in humans and mice using one tool compound called GS720566 we’re able to show that TLR7 activation in immunocompetent mice in the brain leads to accumulation of myeloid cells with an M1 phenotype as well as a small accumulation of cytotoxic T-cells. And so this is an exciting observation suggesting that you can stimulate immune cell ingress into the brain which is normally felt to have a problem for immune cells to enter an immunologically privileged site. And then finally, in the last phase of the investigation, we were able to show that TOL-like receptor agonists can stimulate T-cell accumulation in these tumors and lead to and are associated with regressions of CNS lymphoma pathogenesis in immunocompetent mice and a biopsy model, both by systemic administration and more recently by intratumoral injection of TLR agonists. So the translational potential for this is important because there’s increasing evidence that defects in the adaptive immune response are associated with adverse outcomes in patients that receive chemotherapy. And one would hope that the administration of TLR7-8 agonists could augment the efficacy of chemotherapy and may also be useful in combination with other modalities such as checkpoint blockade as well as CAR T-cell therapy in this disease.

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