Open Access
PD1 signal transduction pathways in T cells
(Impact Journals, 2017) Arasanz Esteban, Hugo; Gato Cañas, María; Zuazo Ibarra, Miren; Ibañez Vea, María; Breckpot, Karine; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. Amongst these therapeutic agents, antibodies that block PD-L1/PD1 interactions between cancer cells and T cells are demonstrating high efficacies and low toxicities. Despite all the recent advances, very little is yet known on the molecular intracellular signaling pathways regulated by either PD-L1 or PD1. Here we review the current knowledge on PD1-dependent intracellular signaling pathways, and the consequences of disrupting PD1 signal transduction.
Open Access
Systemic CD4 immunity: a powerful clinical biomarker for PD-L1/PD-1 immunotherapy
(EMBO Press, 2020) Zuazo Ibarra, Miren; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Vera García, Ruth; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua, BMED 050-2019
The search for non-invasive systemic biomarkers of response to PD-L1/PD-1 blockade immunotherapy is currently a priority in oncoimmunology. In contrast to classical tumor biomarkers, the identification of clinically useful immunological biomarkers is certainly a challenge, as anti-cancer immune responses depend on the coordinated action of many cell types. Studies on the dynamics of systemic CD8 T-cell populations have provided indications that such biomarkers may have a place in clinical practice. However, the power of CD8 T-cell subsets to discriminate clinical responses in immunotherapy has so far proven to be limited. The systemic evaluation of CD8 T-cell regulators such as myeloid cells and CD4 T cells may provide the solution. Here we discuss the value of systemic quantification of CD4 T-cell subsets for patient selection in light of the results obtained by Prof. Kagamu′s and our team. Our studies have independently demonstrated that the evaluation of the pre-treatment status of systemic CD4 immunity is a critical factor for the clinical outcome of PD-L1/PD-1 blockade therapy with robust predictive capacities.
Open Access
A proteomic atlas of lineage and cancer-polarized expression modules in myeloid cells modeling immunosuppressive tumor-infiltrating subsets
(MDPI, 2021) Blanco, Ester; Ibañez Vea, María; Hernández, Carlos; Drici, Lylia; Martínez de Morentin Iribarren, Xabier; Gato Cañas, María; Ausín, Karina; Bocanegra Gondán, Ana Isabel; Zuazo Ibarra, Miren; Chocarro de Erauso, Luisa; Arasanz Esteban, Hugo; Fernández Hinojal, Gonzalo; Fernández Irigoyen, Joaquín; Smerdou, Cristian; Garnica, Maider; Echaide Górriz, Míriam; Fernández Rubio, Leticia; Morente Sancho, Pilar; Ramos-Castellanos, Pablo; Llopiz, Diana; Santamaría Martínez, Enrique; Larsen, Martin R.; Escors Murugarren, David; Kochan, Grazyna; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Ciencias de la Salud; Gobierno de Navarra / Nafarroako Gobernua
Monocytic and granulocytic myeloid-derived suppressor cells together with tumor-infiltrating macrophages constitute the main tumor-infiltrating immunosuppressive myeloid populations. Due to the phenotypic resemblance to conventional myeloid cells, their identification and purification from within the tumors is technically difficult and makes their study a challenge. We differentiated myeloid cells modeling the three main tumor-infiltrating types together with uncommitted macrophages, using ex vivo differentiation methods resembling the tumor microenvironment. The phenotype and proteome of these cells was compared to identify linage-dependent relationships and cancer-specific interactome expression modules. The relationships between monocytic MDSCs and TAMs, monocytic MDSCs and granulocytic MDSCs, and hierarchical relationships of expression networks and transcription factors due to lineage and cancer polarization were mapped. Highly purified immunosuppressive myeloid cell populations that model tumor-infiltrating counterparts were systematically analyzed by quantitative proteomics. Full functional interactome maps have been generated to characterize at high resolution the relationships between the three main myeloid tumor-infiltrating cell types. Our data highlights the biological processes related to each cell type, and uncover novel shared and differential molecular targets. Moreover, the high numbers and fidelity of ex vivo-generated subsets to their natu-ral tumor-shaped counterparts enable their use for validation of new treatments in high-throughput experiments.
Open Access
The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity
(Springer Nature, 2021) Edwards, Carolyn J.; Sette, Angelica; Cox, Carl; Di Fiore, Barabara; Wyre, Chris; Sydoruk, Daniela; Yadin, David; Hayes, Philip; Stelter, Szymon; Bartlett, Phillip D.; Zuazo Ibarra, Miren; García Granda, María Jesús; Benedetti, Giovanni; Fiaska, Stratonik; Birkett, Neil R.; Teng, Yumin; Enever, Carrie; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Fernández Hinojal, Gonzalo; Vera García, Ruth; Archer, Bethan; Osuch, Isabelle; Lewandowska, Martyna; Surani, Yasmin M.; Kochan, Grazyna; Escors Murugarren, David; Legg, James; Pierce, Andrew J.; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako Gobernua
Background: improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. Methods: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. Results: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. Conclusions: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.
Open Access
Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy
(AME Publishing, 2017) Zuazo Ibarra, Miren; Gato Cañas, María; Llorente, Noelia; Ibañez Vea, María; Arasanz Esteban, Hugo; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Programmed cell death-1 (PD1) has become a significant target for cancer immunotherapy. PD1 and its receptor programmed cell death 1 ligand 1 (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B cells amongst other immune cell types. However, cancer cells take advantage of these immunosuppressive regulatory mechanisms to escape T and B cell-mediated immunity. PD1 engagement on T cells by PDL1 on the surface of cancer cells dramatically interferes with T cell activation and the acquisition of effector capacities. Interestingly, PD1-targeted therapies have demonstrated to be highly effective in rescuing T cell anti-tumor effector functions. Amongst these the use of anti-PD1/PDL1 monoclonal antibodies are particularly efficacious in human therapies. Furthermore, clinical findings with PD1/PDL1 blockers over several cancer types demonstrate clinical benefit. Despite the successful results, the molecular mechanisms by which PD1-targeted therapies rescue T cell functions still remain elusive. Therefore, it is a key issue to uncover the molecular pathways by which these therapies exert its function in T cells. A profound knowledge of PDL1/PD1 mechanisms will surely uncover a new array of targets susceptible of therapeutic intervention. Here, we provide an overview of the molecular events underlying PD1-dependent T cell suppression in cancer.