Written by: Jasmin Kumar
Edited by: Ryan Lee
Edited by: Ryan Lee
Immunotherapy is a type of therapy that is used in cancer treatment to boost the body’s immune system so that it can defend itself from cancer more effectively. It helps the immune system detect neoplastic cells, also known as tumorous cells, to trigger an immune response within the body. The body uses many different types of strategies to defend itself from cancer, but a cancerous tumor usually sits in the tumor microenvironment (TME) and ends up inactivating many of the body’s mechanisms like the use of macrophages and natural killer cells, which would usually help in destroying tumors (Sun et al. 2022). Some of the types of immunotherapies include oncolytic viruses, vaccines, pattern recognition receptor targets, or adjuvants. The use of immunotherapy helps to boost immune system surveillance which can also help in regulating the tumor immune microenvironment (TIME) (Sun et al. 2022). New immunotherapy approaches have been developed such as adoptive T cell therapies which include targets like T cell receptors or a chimeric antigen receptor for T-cells and immune checkpoint inhibitors that use antibodies (Sun et al. 2022).
The important part of developing immunotherapy is making sure that the environments are the same when using cancer models to test the different types of immunotherapies. The cancer models that are being utilized need to have the same environment as that of immune cells and other TME components. The interactions between the tumor cells and the non-tumor cells can affect many things in the body like cancer progression, drug resistance, carcinogenesis, or tumor metastasis, so it is important to make sure that the environments are similar to an in vivo environment (Sun et al. 2022). There are models that have been used but do not satisfy these requirements as stated above. Such models include 2D models which do not work well because they do not show all of the parts of the TIME for real human tumors, mice, which cannot be used because the TME is too different from humans to be able to compare them5, and patient derived tumor xenografts (PDTX), which are too time consuming and do not properly replicate the interactions between the cancer cells and the immune system (Begley and Ellis 2012). While a PDTX is usually transplanted into a mouse model, human tumor organoids, on the other hand, are good at preserving tissue architecture with the endogenous components, and specifically, patient-derived organoids can properly model immunotherapy responses and facilitate accurate testing (Sun et al. 2022).
Applications of organoids in immunotherapy include adoptive cell transfer therapy, immune checkpoint inhibitors, and other applications. In adoptive cell transfer therapy, circulating lymphocytes are collected and tumor recognizing antigens are picked or created, which are tested on PDOs. In an experiment done by Michie et al. CAR T cells and birinapant, an inhibitor of apoptosis proteins, were shown to reduce PDO growth while CAR T cells alone were ineffective (Michie et al. 2019). Immune checkpoint inhibitors target PD1/PD-L1, a protein that acts as a break to keep the body’s immune system in check, in advanced tumors, and the dynamic response and resistance to immune checkpoint inhibitors can be replicated through the microfluidic 3D culture. Lastly, there are other applications that organoids can be a part of such as testing the infectivity and cytotoxicity of cancer alone or in combination with chemotherapy (Sun et al. 2022). It can also be used to study the specificity and efficacy of antibody-based immunotherapies. Overall, organoids are very useful tools in studying the different types of therapies for cancer.
There are two types of techniques that organoids are useful for in immunotherapy. They are divided into classifications: holistic approaches or reconstitution approaches, each having multiple different types of techniques that use different methods.
The holistic approach consists of the air-liquid interface (ALI) and the microfluidic 3D culture. ALI uses two dishes: one dish has two layers consisting of a collagen gel matrix and the other consisting of small fragments of organoid tissue. This technique allows for the growth of large fragments of the organoid that maintain the native tissue architecture while also preserving the composition of the TME and any alterations that may arise from the native tumor (Sun et al. 2022). The microfluidic 3D culture creates spheroids from the organoids that have a culture medium that allows for the spheroids to be fed. This type of technique maintains the native cancer tissue complexity and diversity. Microfluidic 3D culture also allows for the studying of the interaction between T cells and the cancer organoids (Sun et al. 2022).
The reconstitution approach consists of the submerged matrigel culture. This technique uses dissociated cancer cells that are mixed with a gel of 3D matrigel. During this process, there are various growth factors and inhibitors that are added to the culture medium, which can also be customized to the experiment (Sun et al. 2022). This method enriches the epithelial tumor cells, but it does not actually preserve the stromal components of the cancer tissue. This technique has been used in many different experiments. One example of the use of submerged matrigel culture was through an experiment done by Forsythe et al. in which the experimenters used a collagen-based matrix to fabricate the patient-derived tumor organoids. From this experiment, it was found that immunocompetent organoids can be used in personalized immunotherapy efficiency through preclinical studies (Forsythe et al. 2021). Another technique that is used for immunotherapy experiments with organoids is the organoid on a chip method. This technique allows for the cultures of the tissues to have no size restrictions that can result in different shapes and sizes. It overcomes the challenge of maintaining the difference in mechanical properties of the organoids, by increasing uniformity and mimicking the physical conditions of the body (Sun et al. 2022).
Using complex organoids for immunotherapy showcases how each technique needs to be adjusted for certain requirements. For example, adding immune components to the organoids differs between the ALI method and the matrigel technique. The presence of immune components was first shown by Zumwalde et al. when it was shown that leukocyte populations differed between breast organoid and peripheral blood (Zumwalde et al. 2016). In ALI, the complex microenvironment is maintained for one to two months and this technique works well in large organoids. On the other hand, the matrigel technique requires immune cells to be added to the culture, but this makes it so that the organoid can be customized to whatever treatment method is being tested (Xia et al. 2021). This exogenous addition, however, does not accurately represent the TME. Another example is that the organoid vascularization and perfusion is a major challenge, as the organoids usually have an absence of vascularization (Sun et al. 2022). Diffusion is also an issue within these techniques because the increase in size of the organoid leads to a decrease in the diffusion of nutrients and essentials within the organoid.
References
Begley CG, Ellis LM, 2012. Drug development: raise standards for preclinical cancer research, Nature, 483:531-3, doi: 10.1038/483531a
Forsythe SD, Erali RA, Sasikumar S, Laney P, Shelkey E, D’Agostino R, Miller LD, Shen P, Levine EA, Soker S, et al, 2021. Organoid platform in preclinical investigation of personalized immunotherapy efficacy in appendiceal cancer: feasibility study. Clin Cancer Res, 27:5141–50. doi: 10.1158/1078-0432.CCR-21-0982
Michie J, Beavis PA, Freeman AJ, Vervoort SJ, Ramsbottom KM, Narasimhan V, Lelliott EJ, Lalaoui N, Ramsay RG, Johnstone RW, et al, 2019. Antagonism of IAPs enhances CAR T-Cell efficacy. Cancer Immunol Res, 7:183–92. doi: 10.1158/2326-6066.CIR-18-0428
Sun C-P, Lan H-R, Fang X-L, Yang X-Y and Jin K-T, 2022. Organoid models for precision cancer immunotherapy. Front. Immunol. 13:770465. doi: 10.3389/fimmu.2022.770465
Xia T, Du WL, Chen XY, Zhang YN, 2021. Organoid models of the tumor microenvironment and their applications. J Cell Mol Med, 25:5829-41, doi: 10.1111/jcmm.16578
Zumwalde NA, Haag JD, Sharma D, Mirrielees JA, Wilke LG, Gould MN, Gumperz, JE, 2016. Analysis of immune cells from human mammary ductal epithelial organoids reveals Vd2+ T cells that efficiently target breast carcinoma cells in the presence of bisphosphonate. Cancer Prev Res 9:305–16. doi: 10.1158/1940-6207.CAPR-15-0370-T
The important part of developing immunotherapy is making sure that the environments are the same when using cancer models to test the different types of immunotherapies. The cancer models that are being utilized need to have the same environment as that of immune cells and other TME components. The interactions between the tumor cells and the non-tumor cells can affect many things in the body like cancer progression, drug resistance, carcinogenesis, or tumor metastasis, so it is important to make sure that the environments are similar to an in vivo environment (Sun et al. 2022). There are models that have been used but do not satisfy these requirements as stated above. Such models include 2D models which do not work well because they do not show all of the parts of the TIME for real human tumors, mice, which cannot be used because the TME is too different from humans to be able to compare them5, and patient derived tumor xenografts (PDTX), which are too time consuming and do not properly replicate the interactions between the cancer cells and the immune system (Begley and Ellis 2012). While a PDTX is usually transplanted into a mouse model, human tumor organoids, on the other hand, are good at preserving tissue architecture with the endogenous components, and specifically, patient-derived organoids can properly model immunotherapy responses and facilitate accurate testing (Sun et al. 2022).
Applications of organoids in immunotherapy include adoptive cell transfer therapy, immune checkpoint inhibitors, and other applications. In adoptive cell transfer therapy, circulating lymphocytes are collected and tumor recognizing antigens are picked or created, which are tested on PDOs. In an experiment done by Michie et al. CAR T cells and birinapant, an inhibitor of apoptosis proteins, were shown to reduce PDO growth while CAR T cells alone were ineffective (Michie et al. 2019). Immune checkpoint inhibitors target PD1/PD-L1, a protein that acts as a break to keep the body’s immune system in check, in advanced tumors, and the dynamic response and resistance to immune checkpoint inhibitors can be replicated through the microfluidic 3D culture. Lastly, there are other applications that organoids can be a part of such as testing the infectivity and cytotoxicity of cancer alone or in combination with chemotherapy (Sun et al. 2022). It can also be used to study the specificity and efficacy of antibody-based immunotherapies. Overall, organoids are very useful tools in studying the different types of therapies for cancer.
There are two types of techniques that organoids are useful for in immunotherapy. They are divided into classifications: holistic approaches or reconstitution approaches, each having multiple different types of techniques that use different methods.
The holistic approach consists of the air-liquid interface (ALI) and the microfluidic 3D culture. ALI uses two dishes: one dish has two layers consisting of a collagen gel matrix and the other consisting of small fragments of organoid tissue. This technique allows for the growth of large fragments of the organoid that maintain the native tissue architecture while also preserving the composition of the TME and any alterations that may arise from the native tumor (Sun et al. 2022). The microfluidic 3D culture creates spheroids from the organoids that have a culture medium that allows for the spheroids to be fed. This type of technique maintains the native cancer tissue complexity and diversity. Microfluidic 3D culture also allows for the studying of the interaction between T cells and the cancer organoids (Sun et al. 2022).
The reconstitution approach consists of the submerged matrigel culture. This technique uses dissociated cancer cells that are mixed with a gel of 3D matrigel. During this process, there are various growth factors and inhibitors that are added to the culture medium, which can also be customized to the experiment (Sun et al. 2022). This method enriches the epithelial tumor cells, but it does not actually preserve the stromal components of the cancer tissue. This technique has been used in many different experiments. One example of the use of submerged matrigel culture was through an experiment done by Forsythe et al. in which the experimenters used a collagen-based matrix to fabricate the patient-derived tumor organoids. From this experiment, it was found that immunocompetent organoids can be used in personalized immunotherapy efficiency through preclinical studies (Forsythe et al. 2021). Another technique that is used for immunotherapy experiments with organoids is the organoid on a chip method. This technique allows for the cultures of the tissues to have no size restrictions that can result in different shapes and sizes. It overcomes the challenge of maintaining the difference in mechanical properties of the organoids, by increasing uniformity and mimicking the physical conditions of the body (Sun et al. 2022).
Using complex organoids for immunotherapy showcases how each technique needs to be adjusted for certain requirements. For example, adding immune components to the organoids differs between the ALI method and the matrigel technique. The presence of immune components was first shown by Zumwalde et al. when it was shown that leukocyte populations differed between breast organoid and peripheral blood (Zumwalde et al. 2016). In ALI, the complex microenvironment is maintained for one to two months and this technique works well in large organoids. On the other hand, the matrigel technique requires immune cells to be added to the culture, but this makes it so that the organoid can be customized to whatever treatment method is being tested (Xia et al. 2021). This exogenous addition, however, does not accurately represent the TME. Another example is that the organoid vascularization and perfusion is a major challenge, as the organoids usually have an absence of vascularization (Sun et al. 2022). Diffusion is also an issue within these techniques because the increase in size of the organoid leads to a decrease in the diffusion of nutrients and essentials within the organoid.
References
Begley CG, Ellis LM, 2012. Drug development: raise standards for preclinical cancer research, Nature, 483:531-3, doi: 10.1038/483531a
Forsythe SD, Erali RA, Sasikumar S, Laney P, Shelkey E, D’Agostino R, Miller LD, Shen P, Levine EA, Soker S, et al, 2021. Organoid platform in preclinical investigation of personalized immunotherapy efficacy in appendiceal cancer: feasibility study. Clin Cancer Res, 27:5141–50. doi: 10.1158/1078-0432.CCR-21-0982
Michie J, Beavis PA, Freeman AJ, Vervoort SJ, Ramsbottom KM, Narasimhan V, Lelliott EJ, Lalaoui N, Ramsay RG, Johnstone RW, et al, 2019. Antagonism of IAPs enhances CAR T-Cell efficacy. Cancer Immunol Res, 7:183–92. doi: 10.1158/2326-6066.CIR-18-0428
Sun C-P, Lan H-R, Fang X-L, Yang X-Y and Jin K-T, 2022. Organoid models for precision cancer immunotherapy. Front. Immunol. 13:770465. doi: 10.3389/fimmu.2022.770465
Xia T, Du WL, Chen XY, Zhang YN, 2021. Organoid models of the tumor microenvironment and their applications. J Cell Mol Med, 25:5829-41, doi: 10.1111/jcmm.16578
Zumwalde NA, Haag JD, Sharma D, Mirrielees JA, Wilke LG, Gould MN, Gumperz, JE, 2016. Analysis of immune cells from human mammary ductal epithelial organoids reveals Vd2+ T cells that efficiently target breast carcinoma cells in the presence of bisphosphonate. Cancer Prev Res 9:305–16. doi: 10.1158/1940-6207.CAPR-15-0370-T
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