The impact of antibody isotype on patient monocyte and macrophage functions and activation states to manipulate anti-tumour responses in melanoma

抗体同种型对患者单核细胞和巨噬细胞功能和激活状态的影响，以操纵黑色素瘤的抗肿瘤反应

• 批准号: MR/V049445/1
• 负责人: Rebecca Adams
• 金额: $ 36.96万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV049445%2F1
• 关键词: impact; antibody; isotype; patient; monocyte

The rates of cutaneous malignant melanoma, the deadliest form of skin cancer, are continuing to increase in the UK despite new therapies available for patients. Melanomas develop when UV radiation from sunlight causes mutations in the DNA of melanocytes, or pigment cells, in the skin, allowing them to multiply, grow, invade local structures and spread to other parts of the body. One reason why melanoma can be so deadly is because cancer cells can create inflammation within the tumour and recruit immune cells which they can control. Macrophages are one such cell type which is found in melanoma tumours. Macrophages normally help our immune system to clear infections and then to restore order in tissues following the destruction caused by invading pathogen. However, we have shown that macrophages can be brought in tumours and these tumour-associated macrophages can be manipulated to help tumours to grow, spread, and together with cancer cells, create an environment which makes it harder for the immune system to fight the cancer. Tumour-associated macrophages are large immune cells found in cancer lesions that have been studied extensively in other cancers but less so in melanoma. The studies which have been undertaken so far have shown that if there are more macrophages in the melanoma tumour, patients with these tumours are more likely to have more advanced disease and have a worse outcome. It is likely that signals from the melanoma cells can change the function of macrophages, causing them to aid melanoma growth and reduce the immune response to the cancer, although the exact mechanisms of these are unknown. In addition to this, monocytes in the blood, which can become macrophages once they arrive in tissues, may be different in patients with melanoma when compared to healthy people, and may display a reduced ability to create an effective immune response against the cancer. This study aims to explore the difference in monocytes in healthy volunteers and patients with melanoma, revealing how monocytes are recruited to the melanoma tumour and how they can be controlled by signals from the melanoma and from the immune system. We ultimately wish to understand how these cells change their function when they encounter monoclonal antibodies. Monoclonal antibodies which recognise targets on cancer cells are part of a growing field of using the body's own immune system to treat cancer. Monoclonal antibodies bind to both targets on cancer cells and receptors on immune cells, triggering responses in these immune cells which ultimately lead to a stronger immune response and killing of the cancer. The binding of antibodies on macrophage receptors may influence the macrophages to become better at killing cancer cells, making treatment more effective. A better understanding of these important cells in the context of melanoma and how they can be awakened by antibodies may uncover not only potential new targets for treatments, but also give us a better understanding of the disease process, and how monoclonal antibodies can be used successfully improve treatment for patients with melanoma.

皮肤恶性黑色素瘤是最致命的皮肤癌，尽管有新的治疗方法，但在英国的发病率仍在继续上升。当来自阳光的紫外线辐射导致皮肤中黑色素细胞或色素细胞的DNA突变时，黑色素瘤就会发生，从而使它们繁殖、生长、侵入局部结构并扩散到身体的其他部位。黑色素瘤如此致命的一个原因是癌细胞可以在肿瘤内产生炎症，并招募它们可以控制的免疫细胞。巨噬细胞是黑色素瘤肿瘤中发现的一种细胞类型。巨噬细胞通常帮助我们的免疫系统清除感染，然后在入侵病原体造成破坏后恢复组织秩序。然而，我们已经证明，巨噬细胞可以被带入肿瘤，这些肿瘤相关的巨噬细胞可以被操纵来帮助肿瘤生长，扩散，并与癌细胞一起创造一个环境，使免疫系统更难对抗癌症。肿瘤相关巨噬细胞是在癌症病变中发现的大型免疫细胞，在其他癌症中已被广泛研究，但在黑色素瘤中研究较少。迄今为止进行的研究表明，如果黑色素瘤肿瘤中有更多的巨噬细胞，这些肿瘤患者更有可能患有更晚期的疾病，并且预后更差。很可能来自黑色素瘤细胞的信号可以改变巨噬细胞的功能，使它们帮助黑色素瘤生长并降低对癌症的免疫反应，尽管这些的确切机制尚不清楚。除此之外，血液中的单核细胞，一旦到达组织中就可以变成巨噬细胞，与健康人相比，黑色素瘤患者的单核细胞可能不同，并且可能显示出对癌症产生有效免疫反应的能力降低。 这项研究旨在探索健康志愿者和黑色素瘤患者单核细胞的差异，揭示单核细胞如何被招募到黑色素瘤肿瘤中，以及它们如何受到来自黑色素瘤和免疫系统的信号的控制。我们最终希望了解这些细胞在遇到单克隆抗体时如何改变其功能。单克隆抗体能够识别癌细胞上的靶点，这是利用人体自身免疫系统治疗癌症的一个不断发展的领域。单克隆抗体与癌细胞上的靶点和免疫细胞上的受体结合，触发这些免疫细胞的反应，最终导致更强的免疫反应和杀死癌症。抗体与巨噬细胞受体的结合可能会影响巨噬细胞，使其更好地杀死癌细胞，使治疗更有效。更好地了解这些重要细胞在黑色素瘤的背景下，以及它们如何被抗体唤醒，不仅可以揭示潜在的新治疗靶点，而且还可以让我们更好地了解疾病过程，以及如何使用单克隆抗体成功地改善黑色素瘤患者的治疗。

项目成果

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma.

• DOI: 10.1038/s41467-023-39042-y
• 发表时间: 2023-06-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Crescioli, Silvia;Correa, Isabel;Ng, Joseph;Willsmore, Zena N.;Laddach, Roman;Chenoweth, Alicia;Chauhan, Jitesh;Di Meo, Ashley;Stewart, Alexander;Kalliolia, Eleni;Alberts, Elena;Adams, Rebecca;Harris, Robert J.;Mele, Silvia;Pellizzari, Giulia;Black, Anna B. M.;Bax, Heather J.;Cheung, Anthony;Nakamura, Mano;Hoffmann, Ricarda M.;Terranova-Barberio, Manuela;Ali, Niwa;Batruch, Ihor;Soosaipillai, Antoninus;Prassas, Ioannis;Ulndreaj, Antigona;Chatanaka, Miyo K.;Nuamah, Rosamund;Kannambath, Shichina;Dhami, Pawan;Geh, Jenny L. C.;Ross, Alastair D. MacKenzie;Healy, Ciaran;Grigoriadis, Anita;Kipling, David;Karagiannis, Panagiotis;Dunn-Walters, Deborah K.;Diamandis, Eleftherios P.;Tsoka, Sophia;Spicer, James;Lacy, Katie E.;Fraternali, Franca;Karagiannis, Sophia N.
• 通讯作者: Karagiannis, Sophia N.

Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician.

• DOI: 10.3390/cancers13225625
• 发表时间: 2021-11-10
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Adams R;Moser B;Karagiannis SN;Lacy KE
• 通讯作者: Lacy KE

Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies.

• DOI: 10.1080/2162402x.2022.2127284
• 发表时间: 2022
• 期刊: Oncoimmunology
• 影响因子: 7.2

Macrophages in ovarian cancer and their interactions with monoclonal antibody therapies.

• DOI: 10.1093/cei/uxab020
• 发表时间: 2022-07-22
• 期刊: Clinical and experimental immunology
• 影响因子: 4.6