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Editor | xi The occurrence and development of tumors are not only related to tumor cells themselves, but immune cells in the tumor microenvironment are also closely related to tumor growth and treatment.
Among them, CD8+ T cells recognize tumor-related antigens through TCR on the cell surface, and then kill tumor cells, forming an important part of anti-tumor immunity.
Checkpoint blockade immunotherapy (checkpoint blockade immunotherapy) depletes the function of CD8+ T cells (exhausted CD8+ T cells) in the tumor microenvironment and promotes the infiltration and proliferation of immune cells, in a variety of cancers including melanoma, non-small cells Significant success has been achieved in the treatment of lung cancer.
The 5-year survival rate of patients with malignant melanoma treated with anti-PD1 and anti-CTLA4 double monoclonal antibodies exceeds 50% [1-3].
Because melanoma shares certain antigens with normal melanocytes, some patients with malignant melanoma undergoing immunotherapy will kill tumor cells as well as their own melanocytes due to immune cells, which in turn develops from the immune disease vitiligo .
And this part of the patients who develop vitiligo during the course of melanoma immunotherapy tends to have a better prognosis than other patients [4].
CD8+ T cells have different subtypes, including effector CD8+ T cells and memory CD8+ T cells.
Although effector T cells have strong cytotoxicity and high lethality, their life span is short, and the cell population will shrink rapidly after proliferation.
Memory CD8+ T cells can survive for a long time and play an important role in immune monitoring of chronic diseases such as tumors.
Memory CD8+ T cells can be divided into central memory CD8+ T cells (TCM) that exist in the blood and secondary lymphoid organs according to their location and function.
The effect memory CD8+ that exists in the blood and peripheral tissues is CD8+ T cell (effector memory CD8+ T cell, TEM), stem cell memory CD8+ T cell (TSCM) with high proliferation and differentiation ability, and those discovered in recent years exist only in a variety of peripheral tissues.
Involved in lymphocyte recycling, resident memory CD8+ T cell (TRM), which plays an important role in the anti-tumor immunity of a variety of solid tumors [5].
In recent years, although there has been a lot of excellent work revealing the important role of different subtypes of CD8+ T cells in immunotherapy and tumor immunity, there is a long-term anti-tumor immune protective response in tumor patients with good prognosis.
Exploration is not lacking yet.
Therefore, revealing the long-acting anti-tumor immune protection mechanism that exists in these cancer survivors is of great significance for better understanding and designing immunotherapy for other patients and tumor types.
March 24, 2021, Dartmouth-Hitchcock Norris Cotton Cancer Center (Dartmouth-Hitchcock Norris Cotton Cancer Center) Mary Jo Turk Immunology Laboratory and the Christina Angeles Team of Surgical Oncology, currently working at the Roger Children’s Cancer Center in Michigan Cooperation (the first author is Han Jichang, Department of Microbiology and Immunology, Dartmouth College) Published an article Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy in Nature Cancer, for a group of patients with vitiligo in immunotherapy CD8+ T cells in survivors of malignant melanoma have been studied in order to reveal the relevant characteristics of important long-term anti-tumor immune protection.
The author collected matched blood, tumor and vitiligo skin tissue samples from each melanoma survivor, and performed single-cell RNA sequencing and single-cell T cells on CD8+ T cells.
Receptor (single-cell TCR sequencing) sequencing.
The results of the experiment first found that the CD8+ T cells in the blood and the CD8+ T cells in the tumor and skin tissues have a different phenotype: central memory CD8+ T cells, effector memory CD8+ T cells and effector CD8+ T cells Mainly exists in the blood, while the resident memory CD8+ T cells and stem memory CD8+ T cells are only found in tumors and skin tissues.
The results of immunohistochemistry and evanescent cytometry also confirmed the same conclusion.
Further analysis of CD8+ T cells with resident memory revealed three different subtypes, among which a group of highly expressing important pro-inflammatory cytokines-interferon (IFNG) and tumor necrosis factor (TNF), was named TRM-IFNG .
The gene signature of this group of cells was found to predict the survival of patients with malignant melanoma, revealing the important role that TRM-IFNG resident memory CD8+ cells may play in the long-term survival of tumor patients.
Although at the level of gene expression, the author has discovered an important immune cell population that may participate in tumor long-term immunity, whether this group of CD8+ T cells can potentially recognize tumor antigens is also an important factor in whether they can exert anti-tumor immunity.
The T cell receptor (TCR) on the surface of CD8+ T cells does not change with cell proliferation and phenotype changes, so the T cell receptor on the clonal proliferation of CD8+ T cells in the tumor can be used as a marker ( clonal expanded CD8+ T cells) to match the T cell receptors on the surface of memory CD8+ T cells in the blood and skin to explore whether CD8+ T cells in non-tumor tissues have the same tumor recognition function.
By analyzing the sequencing data of single-cell T cell receptors, the authors found that many CD8+ T cell clonotypes coexisting in tumors, blood and skin; and CD8+ T cell clonotypes coexisting in blood, skin, and tumors in the skin.
The pro-inflammatory TRM-IFNG resident memory CD8+ T cell phenotype exists, and the gene signature of this group of cells also has the ability to predict the prognosis of patients with melanoma.
The more important question is whether these CD8+ T cells, which show the characteristics of memory T cells in terms of gene expression, can really survive long-term and exert anti-tumor immune function in tumor patients? In order to study the long-term immune protection mechanism of tumors, the author collected a total of 7 melanoma survivors' skin, blood, and skin stored in the pathology department away from the skin, blood sampling for at least 3 years of primary or metastatic melanoma samples, and performed T Cell receptor sequencing (bulk TCRβ DNA sequencing).
By comparing with CD8+ T cell clonotypes in tumor samples, the authors found that tumor-related CD8+ T cell clonotypes can exist in blood and skin for up to 9 years, and skin is more like a tumor than blood The'museum' of related CD8+ T cell clones retains a higher density of tumor-related CD8+ T cells.
Through the integration of single-cell transcriptome data, the authors found that anti-tumor CD8+ T cells that existed for several years existed in the skin as TRM-IFNG resident memory CD8+ T cells, but in the blood with effect memory.
CD8+ cells are present.
This study proved that tumor-related CD8+ T cells exist in the body of tumor survivors in a variety of different memory cell phenotypes, and provide systemic long-term anti-tumor immune protection.
More in-depth research on the dynamic changes of immune cells in tumor patients who respond well to immunotherapy is of great significance for understanding the curative immune response of cancer and how to use such immune response to save more patients with different types of tumors.
Original link: Platemaker: 11 References 1 Hellmann, MD et al.
Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.
N Engl J Med 381, 2020-2031, doi:10.
1056/NEJMoa1910231 (2019).
2 Larkin, J.
et al.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
N Engl J Med 381, 1535-1546, doi :10.
1056/NEJMoa1910836 (2019).
3 Ganesan, A.
-P.
& Ottensmeier, CHH Melanoma-reactive T cells take up residence.
Nature Cancer 2, 253-255, doi:10.
1038/s43018-021-00189-6 (2021 ).
4 Freeman-Keller, M.
et al.
Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes.
Clin Cancer Res 22, 886-894, doi:10.
1158/1078-0432.
CCR -15-1136 (2016).
5 Han, J.
, Khatwani, N.
, Searles, TG, Turk, MJ & Angeles, CVMemory CD8(+) T cell responses to cancer.
Semin Immunol 49, 101435, doi:10.
1016/j.
smim.
2020.
101435 (2020).
Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited with permission, the author has all legal rights, and offenders must be investigated.
Among them, CD8+ T cells recognize tumor-related antigens through TCR on the cell surface, and then kill tumor cells, forming an important part of anti-tumor immunity.
Checkpoint blockade immunotherapy (checkpoint blockade immunotherapy) depletes the function of CD8+ T cells (exhausted CD8+ T cells) in the tumor microenvironment and promotes the infiltration and proliferation of immune cells, in a variety of cancers including melanoma, non-small cells Significant success has been achieved in the treatment of lung cancer.
The 5-year survival rate of patients with malignant melanoma treated with anti-PD1 and anti-CTLA4 double monoclonal antibodies exceeds 50% [1-3].
Because melanoma shares certain antigens with normal melanocytes, some patients with malignant melanoma undergoing immunotherapy will kill tumor cells as well as their own melanocytes due to immune cells, which in turn develops from the immune disease vitiligo .
And this part of the patients who develop vitiligo during the course of melanoma immunotherapy tends to have a better prognosis than other patients [4].
CD8+ T cells have different subtypes, including effector CD8+ T cells and memory CD8+ T cells.
Although effector T cells have strong cytotoxicity and high lethality, their life span is short, and the cell population will shrink rapidly after proliferation.
Memory CD8+ T cells can survive for a long time and play an important role in immune monitoring of chronic diseases such as tumors.
Memory CD8+ T cells can be divided into central memory CD8+ T cells (TCM) that exist in the blood and secondary lymphoid organs according to their location and function.
The effect memory CD8+ that exists in the blood and peripheral tissues is CD8+ T cell (effector memory CD8+ T cell, TEM), stem cell memory CD8+ T cell (TSCM) with high proliferation and differentiation ability, and those discovered in recent years exist only in a variety of peripheral tissues.
Involved in lymphocyte recycling, resident memory CD8+ T cell (TRM), which plays an important role in the anti-tumor immunity of a variety of solid tumors [5].
In recent years, although there has been a lot of excellent work revealing the important role of different subtypes of CD8+ T cells in immunotherapy and tumor immunity, there is a long-term anti-tumor immune protective response in tumor patients with good prognosis.
Exploration is not lacking yet.
Therefore, revealing the long-acting anti-tumor immune protection mechanism that exists in these cancer survivors is of great significance for better understanding and designing immunotherapy for other patients and tumor types.
March 24, 2021, Dartmouth-Hitchcock Norris Cotton Cancer Center (Dartmouth-Hitchcock Norris Cotton Cancer Center) Mary Jo Turk Immunology Laboratory and the Christina Angeles Team of Surgical Oncology, currently working at the Roger Children’s Cancer Center in Michigan Cooperation (the first author is Han Jichang, Department of Microbiology and Immunology, Dartmouth College) Published an article Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy in Nature Cancer, for a group of patients with vitiligo in immunotherapy CD8+ T cells in survivors of malignant melanoma have been studied in order to reveal the relevant characteristics of important long-term anti-tumor immune protection.
The author collected matched blood, tumor and vitiligo skin tissue samples from each melanoma survivor, and performed single-cell RNA sequencing and single-cell T cells on CD8+ T cells.
Receptor (single-cell TCR sequencing) sequencing.
The results of the experiment first found that the CD8+ T cells in the blood and the CD8+ T cells in the tumor and skin tissues have a different phenotype: central memory CD8+ T cells, effector memory CD8+ T cells and effector CD8+ T cells Mainly exists in the blood, while the resident memory CD8+ T cells and stem memory CD8+ T cells are only found in tumors and skin tissues.
The results of immunohistochemistry and evanescent cytometry also confirmed the same conclusion.
Further analysis of CD8+ T cells with resident memory revealed three different subtypes, among which a group of highly expressing important pro-inflammatory cytokines-interferon (IFNG) and tumor necrosis factor (TNF), was named TRM-IFNG .
The gene signature of this group of cells was found to predict the survival of patients with malignant melanoma, revealing the important role that TRM-IFNG resident memory CD8+ cells may play in the long-term survival of tumor patients.
Although at the level of gene expression, the author has discovered an important immune cell population that may participate in tumor long-term immunity, whether this group of CD8+ T cells can potentially recognize tumor antigens is also an important factor in whether they can exert anti-tumor immunity.
The T cell receptor (TCR) on the surface of CD8+ T cells does not change with cell proliferation and phenotype changes, so the T cell receptor on the clonal proliferation of CD8+ T cells in the tumor can be used as a marker ( clonal expanded CD8+ T cells) to match the T cell receptors on the surface of memory CD8+ T cells in the blood and skin to explore whether CD8+ T cells in non-tumor tissues have the same tumor recognition function.
By analyzing the sequencing data of single-cell T cell receptors, the authors found that many CD8+ T cell clonotypes coexisting in tumors, blood and skin; and CD8+ T cell clonotypes coexisting in blood, skin, and tumors in the skin.
The pro-inflammatory TRM-IFNG resident memory CD8+ T cell phenotype exists, and the gene signature of this group of cells also has the ability to predict the prognosis of patients with melanoma.
The more important question is whether these CD8+ T cells, which show the characteristics of memory T cells in terms of gene expression, can really survive long-term and exert anti-tumor immune function in tumor patients? In order to study the long-term immune protection mechanism of tumors, the author collected a total of 7 melanoma survivors' skin, blood, and skin stored in the pathology department away from the skin, blood sampling for at least 3 years of primary or metastatic melanoma samples, and performed T Cell receptor sequencing (bulk TCRβ DNA sequencing).
By comparing with CD8+ T cell clonotypes in tumor samples, the authors found that tumor-related CD8+ T cell clonotypes can exist in blood and skin for up to 9 years, and skin is more like a tumor than blood The'museum' of related CD8+ T cell clones retains a higher density of tumor-related CD8+ T cells.
Through the integration of single-cell transcriptome data, the authors found that anti-tumor CD8+ T cells that existed for several years existed in the skin as TRM-IFNG resident memory CD8+ T cells, but in the blood with effect memory.
CD8+ cells are present.
This study proved that tumor-related CD8+ T cells exist in the body of tumor survivors in a variety of different memory cell phenotypes, and provide systemic long-term anti-tumor immune protection.
More in-depth research on the dynamic changes of immune cells in tumor patients who respond well to immunotherapy is of great significance for understanding the curative immune response of cancer and how to use such immune response to save more patients with different types of tumors.
Original link: Platemaker: 11 References 1 Hellmann, MD et al.
Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.
N Engl J Med 381, 2020-2031, doi:10.
1056/NEJMoa1910231 (2019).
2 Larkin, J.
et al.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
N Engl J Med 381, 1535-1546, doi :10.
1056/NEJMoa1910836 (2019).
3 Ganesan, A.
-P.
& Ottensmeier, CHH Melanoma-reactive T cells take up residence.
Nature Cancer 2, 253-255, doi:10.
1038/s43018-021-00189-6 (2021 ).
4 Freeman-Keller, M.
et al.
Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes.
Clin Cancer Res 22, 886-894, doi:10.
1158/1078-0432.
CCR -15-1136 (2016).
5 Han, J.
, Khatwani, N.
, Searles, TG, Turk, MJ & Angeles, CVMemory CD8(+) T cell responses to cancer.
Semin Immunol 49, 101435, doi:10.
1016/j.
smim.
2020.
101435 (2020).
Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited with permission, the author has all legal rights, and offenders must be investigated.
