Biology subjects

Rannikko, J. H.

Publications and source records attributed to Rannikko, J. H..

4 recordsLinked to original sources

bioRxiv2026

YAP/TEAD drives treatment-induced adaptive immunosuppression in EGFR-mutant lung cancer

Residual disease remains a major obstacle for achieving durable responses in patients treated with oncogene-targeted therapy. Drug-tolerant persister (DTP) cells emerging under treatment and persisting in residual tumors are considered to be the root of acquired resistance, yet their contribution to immune evasion in on-treatment tumors is poorly defined. Here, we show in the context of EGFR-mutant lung cancer that DTP cells actively contribute to the formation of an immunosuppressive tumor microenvironment during EGFR tyrosine kinase inhibitor (TKI) therapy. In syngeneic mouse models and in patients, EGFR TKI therapy leads to an accumulation of immunosuppressive macrophages, which is strictly treatment-dependent and fully reversible upon treatment cessation or progressive disease, respectively. Quiescent DTP cells directly drive the recruitment and immunosuppressive reprogramming of monocytes and macrophages through a YAP-driven secretome, and the DTP-reprogrammed monocytes suppress T cell proliferation and effector functions in vitro. Co-targeting YAP with a TEAD inhibitor ORM-47286 rewires the DTP secretome and inhibits macrophage reprogramming in vitro, and prevents immunosuppressive macrophage accumulation and improves the efficacy of EGFR TKI therapy in immunocompetent mouse models. Our findings highlight the previously unappreciated role of DTP cells in modulating the tumor microenvironment in on-treatment tumors, and position the treatment-induced YAP/TEAD activity in DTP cells as an important driver of adaptive immunosuppression during EGFR-targeted therapy.

cancer biology↗

bioRxiv2024

Secreted Clever-1 Modulates T Cell Responses and Impacts Cancer Immunotherapy Efficacy

Clever-1 functions as a scavenger and adhesion receptor, promoting tolerogenic activities in macrophages and subsets of endothelial cells, thereby contributing to cancer progression. High Clever-1 expression associates with resistance to immune checkpoint inhibitors and combined targeting of Clever-1 with anti-PD-1 enhances response in refractory mouse tumor models. A Clever-1-targeting humanized IgG4 antibody, bexmarilimab, is investigated in clinical trials as a macrophage-reprogramming therapy to treat solid tumors (NCT03733990) and hematological malignancies (NCT05428969). Here we describe a secreted form of (s)Clever-1 enriched in plasma of cancer patients, that was decreased upon bexmarilimab treatment. With the production of a recombinant sClever-1, mimicking the one found in human plasma, we show that sClever-1 can selectively bind activated T cells and disrupt T cell receptor signalling leading to impaired Th1 expansion. We demonstrate that sClever-1 binds to insulin growth factor 2 receptor (IGF2R) on T cells via its mannose-6-phosphate modification and further show that sClever-1 contributes to the immunosuppressive properties of macrophage-secreted extracellular vesicles, driving T cell tolerance and impairing anti-PD-1 efficacy. These findings suggest that Clever-1 exerts a systemic immunosuppressive effect independently of the cells it is expressed on, highlighting its potential as a target in cancer immunotherapy and a valuable biomarker for disease detection.

immunology↗

bioRxiv2024

Patient-derived tumor explant models of tumor immune microenvironment reveal distinct and reproducible immunotherapy responses

Tumor-resident immune cells play a crucial role in eliciting anti-tumor immunity and immunomodulatory drug responses, yet these functions have been difficult to study without tractable models of tumor immune microenvironment (TIME). Patient-derived ex vivo models contain authentic resident immune cells and therefore, could provide new mechanistic insights into how TIME responds to tumor or immune cell-directed therapies. Here, we assessed the reproducibility and robustness of immunomodulatory drug responses across two different ex vivo models of breast cancer TIME and one of renal cell carcinoma. These independently developed TIME models were treated with a panel of clinically relevant immunomodulators, revealing remarkably similar changes in gene expression and cytokine profiles among the three models in response to T cell activation and STING-agonism while still preserving individual patient-specific response patterns. Moreover, we found two common core signatures of adaptive or innate immune responses present across all three models and both types of cancer, potentially serving as a benchmark for drug-induced immune activation in ex vivo models of TIME. The robust reproducibility of immunomodulatory drug responses observed across diverse ex vivo models of TIME underscores the significance of human patient-derived models in elucidating the complexities of antitumor immunity and therapeutic interventions.

immunology↗

bioRxiv2023

Respiratory Complex I Regulates Dendritic Cell Maturation in Explant Model of Human Tumor Immune Microenvironment

Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. Here we establish a Patient-Derived Explant Culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+ T cell cytotoxic activity. We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax + metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+ T cells and thus facilitating anti-tumor immunity. Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

cancer biology↗