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Our Research Interests

Meet below four key protagonists of our research program! At first glance in H&E preparations, lymphoid organs look like "a chaotic sea of cells swimming around in a gelatinous matrix"! But in reality, the level of organization, hierarchy and complexities rising from a spectrum of immunological/hematopoietic events and reactions taking place in these microenvironments are beyond imagination!... In our laboratory, we are particularly intrigued in investigating the effects of cytotoxic chemotherapies in these microenvironments, along with the short- and long-term consequences they may have in peripheral and antitumor immunity!

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Theme 1 - Chemotherapy-Induced Prometastatic Niches: Supporting Alcoves For Breast Cancer Cell Dissemination, Stemness and Immunoediting

Metastatic dissemination occurs at specialized, tripartite microanatomical niches composed of a tumor cell, an endothelial cell and a perivascular macrophage that expresses the receptor tyrosine kinase Tie2, known as "Tumor MicroEnvironment of Metastasis" (TMEM) doorways. TMEM doorways function as the active gateways of metastasizing tumor cells to the circulation, and primarily exert their functions via localized and transient secretion of vascular endothelial growth factor-A (VegfA) in Tie2-dependent manner. Migratory cancer cells are engaged in a "streaming" migration, dependent on physical interactions with intratumoral macrophages, and are driven towards underlying TMEM doorways, where they eventually gain access to the peripheral circulation. This mechanism is described in more detail in a mini-review article, published in the Journal of Cell Science.

In our Science Translational Medicine article, we show that chemotherapy triggers influx of Tie2+ macrophages in the primary breast tumor microenvironment, which subsequently promotes the assembly of TMEM doorways. Moreover, chemotherapy recruits intratumoral macrophages that support the migratory cancer cell phenotype, via the induction of cancer cell streaming and invasion. As a proof-of-principle, the pharmacological elimination of macrophages (e.g. via clodronate liposomes), or Tie2 inhibition, can both counteract the prometastatic effects of chemotherapy, thus suggesting a critical role of the prometastatic macrophages in this context. If you are interested to learn more, refer to the following reviews from our group: Cancer Research, Journal of Leukocyte Biology, and Clinical and Experimental Metastasis.

Our research has indicated that prometastatic (perivascular and/or streaming) macrophages can suppress cytotoxic T cell trafficking and functions within the dissemination trajectories, thus excluding antitumor immunity towards the proliferation compartment (see illustration above). Although these observations can partially explain why natural (and induced/engineered) immunity fails to destroy disseminating tumor cell subpopulations within the "dissemination trajectories", the precise microenvironmental cues responsible for contextual "immuno-subversion" remain largely unknown. Our preliminary data have revealed certain key chemotactic and developmental/morphogenetic pathways, involved in the process.. By elucidating the mechanistic underpinnings behind these processes, we will be able to develop targeted approaches that either enhance natural antitumor immunity, or support induced/engineered approaches (i.e., classical or modern immunotherapies) to eliminate cancer metastasis.

Theme 2 - Chemotherapy-Induced Immunotoxicity: Impact on Primary and Secondary Lymphoid Organ Function & Mechanistic Relevance to Metastasis

Chemotherapy exerts its cytotoxic functions via eliminating rapidly-dividing cells in the body, principally in sites of increased proliferative activity, such as for example all sites of hematopoiesis. In general, both primary (bone marrow and thymus) and secondary (spleen, lymph nodes and MALT) lymphoid organs represent sites of context-dependent, coordinated hematopoietic cell proliferation and maturation, and thus, are among those most prominently affected by chemotherapy-induced cytotoxicity. In many preclinical settings and certain clinical scenarios, lymphoid tissues have been found to undergo temporary, yet quite extreme, dynamic and morphologic changes (i.e. atrophy, fibrosis, etc), following repeated rounds of cytotoxic cancer chemotherapy. In our laboratory, we wish to study how chemotherapy-driven pathologic changes on primary/secondary lymphoid organs may elicit direct consequences on both antitumor immunity and the ensuing process of metastatic dissemination. Below, we outline two key research questions, in more detail:

Question 1 - Chemotherapy Disrupts the Educational
Mission of Thymic Microenvironments

The thymus is a specialized primary lymphoid organ for T cell development and maturation. Our current  understanding on the overall role of the thymus in establishing antitumor immunity comes from observations that age-related thymic involution is associated with poor CD8+ cytotoxic T-cell influx and a concurrent increase of immunosuppressive T-reg cells in the tumor microenvironment, which adequately explains the higher incidence of cancer in older ages.

However, it is well-known that childhood cancer survivors tend to develop severe side-effects later in their lives as a result of receiving chemotherapy treatment for the pediatric tumors they had in the past. Prominent side-effects include health problems in their cardiovascular, respiratory, nervous, endocrine, genitourinary, myoskeletal, and gastrointestinal systems. Moreover, childhood cancer survivors present with higher risk of developing a second cancer in their lives, and respond very poorly to the resolution of inflammation.

It is very likely that pediatric patients receiving cytotoxic chemotherapy may have developed a suboptimal array of T cell repertoires and immune cell imbalances, as a result of impaired thymic functions and thymic atrophy due to chemotherapy treatment. A chemotherapy-diminished T cell repertoire seems to be incapable of effective regulation of inflammation and tumor immunosurveillance, offering a working hypothesis for the observed increased incidence of secondary malignancies in childhood cancer survivors.  By investigating chemotherapy-driven disturbances of thymic microenvironments at the molecular/cellular level, we aim at developing therapeutic interventions for accelerating thymic recovery following chemotherapy-induced acute thymic involution.

Question 2 - Chemotherapy Promotes Immunosuppressive Extramedullary Myelopoiesis

Via secreting trophic factors, cancer cells are notoriously known to skew hematopoiesis towards immunosuppressive myelopoiesis. These myeloid cell populations [Tumor-associated macrophages (TAMs); Tumor-associated neutrophils (TANs); Myeloid-derived suppressor cells MDSCs)] can infiltrate primary and secondary tumor microenvironments, to support cancer cell growth and metastasis, while simultaneously suppressing antitumor immunity. Interestingly, although tumor-promoting myelopoiesis has been reported primarily in the bone marrow, other prominent sites of extramedullary hematopoiesis (EMH) have been desribed.

The spleen has been described as the most sensitive site of "emergency" hematopoiesis. Indeed, a plethora of solid carcinomas are known to sustain tumor-promoting splenic EMH. However, the spleen is not currently seen as simply a "supplement" to bone marrow-mediated hematopoiesis, but primarily as a reservoir of specialized myeloid cell subsets with unique immunosuppressive properties, when infiltrating the tumor microenvironment.


Indeed, an emergency stress response triggered from chemotherapy treatment (e.g., cyclophosphamide), has been shown to significantly enhance splenic EMH with a profound bias towards myelopoiesis. However, the precise molecular/cellular pathways regulating these processes are largely unknown. By investigating the contextual prerequisites and cellular/molecular pathways leading to chemotherapy-driven splenic EMH, we try to develop therapeutic interventions (i.e., anti-myelopoiesis immunotherapy) to disrupt the key source of the immunosuppressive niches in the primary tumor microenvironment.

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