Periodic Reporting for period 1 - ECONOMY (Endothelial Cells - an Overlooked Non-hematopoietic cOmponent of tuMor immunitY)
Période du rapport: 2021-08-01 au 2023-07-31
In this study, we analyzed the interactions of endothelial cells with immune cells in the context of lung cancer.
Immune cells are the body’s natural defense against harmful substances and microorganisms, as well as abnormal tumor cells arising in the body. However, their ability to fight tumor cells is often hampered by interactions with other cell types and factors secreted to the environment around the tumor that can render these immune cells inert. Many cancer therapies are designed to re-activate the immune cells, and thereby activate the body’s own defense mechanism against the tumor (so-called immunotherapies). Although such treatments have proven successful in some cancer patients, these therapies often encounter resistance in the majority of cases. Furthermore, in cases of intital treatment success, patients often relapse later on. To improve these therapies, it is necessary to gain a better understanding of how immune cells are impacted by the cells surrounding them.
Endothelial cells are the cells that line the inner walls of blood vessels, and therefore function as a barrier between the tumor and the blood stream, where the immune cells are recruited from. Thus, immune cells have to pass through the endothelial cell layer to reach the tumor. Potential interactions between endothelial cells and immune cells could therefore be very significant, as they may change the characteristics of immune cells before they encounter the tumor cells. Very interestingly, it has been observed that endothelial cells express proteins that are known to modulate the immune system (so-called immunoregulatory proteins). This was surprising, because such molecules are usually only found on different types of immune cells, or on cancer cells. However, it remains unknown if endothelial cells could interact with immune cells via these proteins.
In our study, we investigated the role of endothelial cells expressing immunoregulatory proteins in tumors. We studied their interactions with immune cells, and examined how those impacted tumor growth and the response to immunotherapy. Using animal models of lung cancer, we identified a potential biomarker that may predict the response of the tumor to immunotherapy (see below). Currently our results are validated in clinical samples. Our results will ultimately (a) help to better identify the patients most likely to respond to immunotherapy, and (b) lead to future work involving modulating the tumor immunity by altering the endothelial barrier to enhance the efficacy of immunotherapies.
Immune cells are the body’s natural defense against harmful substances and microorganisms, as well as abnormal tumor cells arising in the body. However, their ability to fight tumor cells is often hampered by interactions with other cell types and factors secreted to the environment around the tumor that can render these immune cells inert. Many cancer therapies are designed to re-activate the immune cells, and thereby activate the body’s own defense mechanism against the tumor (so-called immunotherapies). Although such treatments have proven successful in some cancer patients, these therapies often encounter resistance in the majority of cases. Furthermore, in cases of intital treatment success, patients often relapse later on. To improve these therapies, it is necessary to gain a better understanding of how immune cells are impacted by the cells surrounding them.
Endothelial cells are the cells that line the inner walls of blood vessels, and therefore function as a barrier between the tumor and the blood stream, where the immune cells are recruited from. Thus, immune cells have to pass through the endothelial cell layer to reach the tumor. Potential interactions between endothelial cells and immune cells could therefore be very significant, as they may change the characteristics of immune cells before they encounter the tumor cells. Very interestingly, it has been observed that endothelial cells express proteins that are known to modulate the immune system (so-called immunoregulatory proteins). This was surprising, because such molecules are usually only found on different types of immune cells, or on cancer cells. However, it remains unknown if endothelial cells could interact with immune cells via these proteins.
In our study, we investigated the role of endothelial cells expressing immunoregulatory proteins in tumors. We studied their interactions with immune cells, and examined how those impacted tumor growth and the response to immunotherapy. Using animal models of lung cancer, we identified a potential biomarker that may predict the response of the tumor to immunotherapy (see below). Currently our results are validated in clinical samples. Our results will ultimately (a) help to better identify the patients most likely to respond to immunotherapy, and (b) lead to future work involving modulating the tumor immunity by altering the endothelial barrier to enhance the efficacy of immunotherapies.
We analyzed the role of two different potential immunoregulatory proteins (protein A and protein B; due to institutional guidelines, I cannot disclose the names of the proteins before publication) on endothelial cells in lung cancer. To this end, we utilized mice that have a genetic alteration causing the absence of either protein A or B, specifically in endothelial cells (we call these mice ECKO mice (endothelial specific conditional knockout mice). We implanted these mice, as well as mice without any genetic alterations (wildtype mice) with lung cancer cells, which enabled us to follow lung cancer development under normal conditions (in wildtype mice) and in the absence of either protein A or B on endothelial cells (in ECKO mice). This experimental set-up allowed us to assess the roles of either protein in tumorigenesis and during immunotherapy response.
Interestingly, we found that protein A plays very important roles in lung tumor growth. In mice lacking protein A on endothelial cells only, the immune cell composition in tumors was significantly different than in wildtype mice. In particular, T-cells (one of the immune cell types responsible for tumor cell killing) were less activated, and consequently tumor growth was increased in ECKO mice, compared to wildtype mice. We demonstrated that in wildtype mice, T cells are modulated when they encounter endothelial cells before entrance into the tumor. This modulation was missing in ECKO mice. While we are still finalizing the study (see below), our results have shown an important role of protein A in endothelial cells. Upon completion of our study we anticipate to validate the expression of protein A on endothelial cells to serve as an independent predictive biomarker for immunotherapy response.
We also studied the roles of protein B in lung cancer using similar models as for protein A. While we observed some interesting changes in lung tumor growth when protein B was absent on endothelial cells, we focused our efforts in the lung cancer models on protein A, as our obtained results were more impactful.
Lastly, we investigated the the roles of the two proteins in melanoma (skin cancer) using ECKO mouse models implanted with melanoma cells, to compare our results in lung cancer to another cancer type that is also commonly treated with immunotherapy. In the context of melanoma, we observed significant influence of protein B on tumor growth and immune cell composition, while no effects could be attributed to protein A. Thus, we observed different functions of protein A and B in different tumor types, further contributing to our understanding of diversity between different types of cancer.
Interestingly, we found that protein A plays very important roles in lung tumor growth. In mice lacking protein A on endothelial cells only, the immune cell composition in tumors was significantly different than in wildtype mice. In particular, T-cells (one of the immune cell types responsible for tumor cell killing) were less activated, and consequently tumor growth was increased in ECKO mice, compared to wildtype mice. We demonstrated that in wildtype mice, T cells are modulated when they encounter endothelial cells before entrance into the tumor. This modulation was missing in ECKO mice. While we are still finalizing the study (see below), our results have shown an important role of protein A in endothelial cells. Upon completion of our study we anticipate to validate the expression of protein A on endothelial cells to serve as an independent predictive biomarker for immunotherapy response.
We also studied the roles of protein B in lung cancer using similar models as for protein A. While we observed some interesting changes in lung tumor growth when protein B was absent on endothelial cells, we focused our efforts in the lung cancer models on protein A, as our obtained results were more impactful.
Lastly, we investigated the the roles of the two proteins in melanoma (skin cancer) using ECKO mouse models implanted with melanoma cells, to compare our results in lung cancer to another cancer type that is also commonly treated with immunotherapy. In the context of melanoma, we observed significant influence of protein B on tumor growth and immune cell composition, while no effects could be attributed to protein A. Thus, we observed different functions of protein A and B in different tumor types, further contributing to our understanding of diversity between different types of cancer.
The findings of our study hold significant implications:
(a) The discovery of distinct functional roles of proteins A and B in different cancer types advances our knowledge of the interactions between various cell types in different tumor contexts. This will further contribute to finding cancer type-specific biomarkers and interventions.
(b) Importantly, our observations regarding the roles of protein A in lung cancer may contribute to our understanding of so-called therapeutic windows for immunotherapy. Many clinical studies have shown that only when T-cells are present in a specific state, immunotherapy works most efficiently in patients. In our study, we show that the interaction with endothelial cells alters the state of T-cells, and thus impacts the therapeutic window. Additional experiments are currently designed to modulate endothelial cells and thereby create an immune environment for optimal immunotherapy treatment.
(a) The discovery of distinct functional roles of proteins A and B in different cancer types advances our knowledge of the interactions between various cell types in different tumor contexts. This will further contribute to finding cancer type-specific biomarkers and interventions.
(b) Importantly, our observations regarding the roles of protein A in lung cancer may contribute to our understanding of so-called therapeutic windows for immunotherapy. Many clinical studies have shown that only when T-cells are present in a specific state, immunotherapy works most efficiently in patients. In our study, we show that the interaction with endothelial cells alters the state of T-cells, and thus impacts the therapeutic window. Additional experiments are currently designed to modulate endothelial cells and thereby create an immune environment for optimal immunotherapy treatment.