Dissecting the interplay between immunoglobulin G and the gut microbiome in cancer progression and metastasis

摘要 癌症进展和转移是癌症相关死亡的主要原因，然而 癌症克服免疫系统的转移才刚刚开始被人们所了解。这个 免疫疗法的前景已经强调了宿主免疫细胞在 控制癌症进展和肠道微生物群在调节反应中的关键作用 为了免疫疗法。然而，我们还没有确定肠道微生物免疫系统是如何 相互作用调节癌症转移，识别与转移风险相关的肠道微生物， 或者改变免疫治疗模式，主动攻击潜在的转移。 最近的研究强调了B细胞在肿瘤进展的免疫调节中的作用，因为肿瘤- B细胞的渗入与免疫治疗的改善和 预后良好。然而，抗肿瘤和促肿瘤B细胞的共存 癌症进展过程中的群体使研究细胞因子功能的途径复杂化 肿瘤浸润性B细胞。由于免疫球蛋白G(Ig G)抗体介导的清除 病原体和肿瘤细胞具有很高的亲和力和特异性，我们最近发现，免疫球蛋白 我们建议，抗体针对特定的肠道细菌，在稳定状态下调节肠道微生物群。 体液免疫在肿瘤抗肿瘤反应中作用的重点研究 进步。我们推测，免疫球蛋白和肠道微生物群之间的相互作用将在 通过塑造肿瘤免疫来阻碍肿瘤进展过程中明确定义的连续步骤 微环境以及全身抗肿瘤反应。因此，我们将使用一种新的模型 曾博士发展免疫球蛋白G缺乏症剖析免疫球蛋白G的特殊作用 在阻碍肿瘤进展中的产生，独立于其他B细胞功能，并对 研究免疫球蛋白对肿瘤的反应如何调节肠道微生物群，从而影响 抗肿瘤免疫。免疫球蛋白G在肿瘤进展中的作用尚不清楚 系统评估，特别是在转移前、微转移或大转移期间。 肿瘤转移的转移分期。此外，肠道微生物群和肠道微生物群之间的相互作用 B细胞亚群、抗肿瘤体液免疫和记忆性B细胞谱系的发展 仍未被开发。我们建议将新型的缺乏免疫球蛋白的动物模型与Well相结合。 特征化的肿瘤模型以及全面的表型和功能表征 相关的免疫亚群将使这个跨学科的团队能够剖析抗体在 肿瘤进展和确定肠道微生物群和免疫球蛋白之间的相互作用如何形成 抗肿瘤免疫与癌症进展。

ABSTRACT Cancer progression and metastasis account for the majority of cancer- related deaths, yet how cancer overcomes the immune system to metastasize is only beginning to be understood. The promise of immunotherapies has underscored how integral the host immune cells are in controlling cancer progression and the critical role of the gut microbiome in modulating responses to immunotherapies. However, we have yet to determine how gut microbiome-immune system interactions modulate cancer metastasis, identify gut microbes associated with metastatic risk, or shift immunotherapy paradigms to proactively attack potential metastases. Recent studies highlighted the role of B cells in immune regulation of tumor progression, as tumor- infiltrating B cells positively associated with improved responses to immunotherapies and favorable prognosis. However, the co-existence of both anti- and pro-tumorigenic B cell populations during cancer progression complicates the approach to studying the functions of tumor-infiltrating B cells. Since immunoglobulin G (IgG) antibodies mediate clearance of pathogens and tumor cells with high affinity and specificity and we recently showed that IgG antibodies target specific gut bacteria, modulating the gut microbiome at steady state, we propose a focused approach to dissect the role of humoral immunity in anti-tumor responses during tumor progression. We hypothesize that the interplay between IgG and gut microbiome will be critical in hindering well defined, sequential steps during tumor progression by shaping the tumor immune microenviroment as well as systemic anti-tumor responses. Thus, we will use a novel model of immunoglobulin G (IgG) deficiency developed by Dr. Zeng to dissect the specific role of IgG production in hindering tumor progression, independent of that of other B cell functions, and to investigate how IgG response to the tumor modulates the gut microbiome and thereby affecting anti-tumor immunity. The role of immunoglobulin G in tumor progression has not yet been systematically evaluated, especially during the pre-metastatic, micro-metastatic or macro- metastatic stages of tumor metastasis. Moreover, the interplay between the gut microbiome and B cell subsets, the development of anti-tumor humoral immunity and memory B cell repertoires remain unexplored. We propose that combining the novel animal model lacking IgG with well characterized tumor models and comprehensive phenotypic and functional characterization of relevant immune subsets will allow this interdisciplinary team to dissect the role of antibodies in cancer progression and determine how the interplay between the gut microbiome and IgG shapes anti-tumor immunity and cancer progression.