Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the therapeutic response is highly heterogeneous. A potential mode of resistance is tumor-intrinsic mechanisms leading to an immunosuppressive tumor microenvironment. However, the underlying interactive network remains elusive and the generalizable biomarkers and targeting strategies are still lacking. Here, we uncovered the potential of plasma S100 calcium-binding protein A1 (S100A1) in determining ICB efficacy based on liquid biopsy of patients with lung cancer. Muti-omics and functional studies suggested that tumor-intrinsic S100A1 expression correlates with an immunologically cold TME and resistance to ICB. Mechanistic investigations demonstrated that interfering with tumor-intrinsic S100A1/ubiquitin-specific protease 7/p65/granulocyte-macrophage colony-stimulating factor (GM-CSF) modulatory axis could potentiate an inflamed TME via promoting M1-like macrophage polarization and T cell function. GM-CSF priming was sufficient to enhance ICB response in tumors with high S100A1 expression. These findings defined S100A1 as a potential biomarker and a novel synergistic target for cancer immunotherapy.
Project description:A number of reports have demonstrated that tumor-intrinsic mechanisms of resistance, such as the loss of genes critical for antigen presentation and inflammatory responses, along with the activation of various cellular signaling cascades, can limit the efficacy of immunotherapy. Strategies to sensitize tumor cells to immunotherapy may overcome some resistance mechanisms, but identifying therapeutic targets has remained challenging. Here, we integrate a two-cell type (2CT) whole-genome CRISPR-Cas9 screen with dynamic transcriptional profiling of the tumor/T cell interaction to comprehensively identify tumor genes that are induced to promote tumor survival. We assessed the therapeutic potential of pharmacological inhibition of these and other top CRISPR identified targets as combinatorial targets to improve the efficacy of tumor destruction by T cells.
Project description:Despite approval of immunotherapy for the treatment of ovarian cancer patients, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in ovarian cancer , we firstly performed an unbiased genome-wide CRISPR immune screens to explore tumor intrinsic factors which regulates ovarian cancer cell lines response to T cell mediated killing. Then we integrated the in vitro CRISPR screen results with multi-omics clinical data to generate a sub-library including top candidates for in vivo CRISPR screen to further evaluate the role of potential tumor intrinsic factors in regulating ovarian cancer cell response to immunotherapy with using the immune checkpoint blocker. Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.
Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.