Source: School of Life Sciences
Written by: School of Life Sciences
Edited by: Wang Dongmei

On August 16, 2016, the research group of Prof. Dong-Ming Kuang at Sun Yat-sen University had an article entitled “Polarization of Tissue-Resident T_FH-Like Cells in Human Hepatoma Bridges Innate Monocyte Inflammation and M2b Macrophage Polarization” published in Cancer Discovery (Impact Factor: 19.8). This is the second paper Prof. Kuang’s team scored in the top journal of American Association for Cancer Research (AACR), with the first one merely three months earlier (OnlineFirst in March) identifying a novel regulatory B cell subset that suppressed antitumor immunity^[1]. This time, the team has unveiled crucial adaptive immune processes that connect innate inflammatory responses and distinct tumor-promoting features of monocytes/macrophages in hepatocellular carcinoma (HCC)^[2].

In previous studies, Prof. Kuang and fellow researchers have established the various immunoediting strategies of tumors that foster immune privilege and chronic inflammation. Nevertheless, the humoral components and their maturation and functions in the tumor microenvironment remain largely elusive. Kuang’s team collaborated with Prof. Xiang-Ming Lao from Sun Yat-sen University Cancer Center on B cell research since 2010. After elucidating the major infiltration mechanism of B cells in HCC^[3] last year and revealing the novel PD-1^hi regulatory B cells^[1] earlier this year, they focused on the development of immunoglobulin-secreting plasma cells in tumor. According to their newly published article^[2], the differentiation of plasma cells could be strongly induced by inflammation-expanded IL-21⁺ T helper cells (coined “T_FH-like cells”, based on their resemblance to follicular helper T cells aka T_FH cells), a series of responses similar but not identical to those in the lymph node. Intriguingly, these responses were found initiated by tumor-activated monocytes and in turn led to M2b-type polarization of monocytes/macrophages, hence forming an adaptive “bridge” that linked two innate processes and eventually resulted in tumor progression.

The key findings include the following: 1) T_FH-like cells were the major source of IL-21 in HCC tumors and represented about 10% of the CD4+ T cell population, but they displayed a unique CXCR5−PD-1^low/−BTLA−CD69^high tissue-resident phenotype with substantial IFN-γ production, which differed from the phenotype of TFH cells in lymph nodes; 2) TLR4-elicited innate monocyte inflammation was important for IL-21⁺ T_FH-like cell expansion in tumors, and activation of STAT1 and STAT3 was critical for T_FH-like cell polarization in this process; 3) the T_FH-like cells operated in IL-21–IFN-γ-dependent pathways to foster plasma cell differentiation and thereby induced protumorigenic M2b macrophage polarization via IgG/FcγII receptor signals. These results are among the first that demonstrated the existence, regulation, and physiological functions of IL-21⁺ cells in tumor, as well as the perplexing cancer-promoting role of antibody production by tumor B cells. With the advancement of monoclonal antibody therapies and their clinical application, data on humoral immunity in human tumor models have become ever more valuable. In addition, studies like this that unravel the complex interaction network of the tumor stromal components are both essential and necessary for the design of novel and more effective therapeutic approaches.


References
[1] Xiao X^#, Lao XM^#, Chen MM^#, Liu RX, Wei Y, Ouyang FZ, Chen DP, Zhao XY, Zhao Q, Li XF, Liu CL, Zheng L, Kuang DM*. 2016. PD-1^hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov. 6:546–559. ^#Co-first authors. *Corresponding author.

[2] Chen MM^#, Xiao X^#, Lao XM^#, Wei Y, Liu RX, Zeng QH, Wang JC, Ouyang FZ, Chen DP, Chan KW, Shi DC, Zheng L, Kuang DM*. 2016. Polarization of tissue-resident T_FH-like cells in human hepatoma bridges innate monocyte inflammation and M2b macrophage polarization. Cancer Discov. Published OnlineFirst August 16, 2016; doi:10.1158/2159-8290.CD-16-0329. #Co-first authors. *Corresponding author.

[3] Liu RX, Wei Y, Zeng QH, Chan KW, Xiao X, Zhao XY, Chen MM, Ouyang FZ, Chen DP, Zheng L, Lao XM, Kuang DM*. 2015. Chemokine (C-X-C motif) receptor 3-positive B cells link interleukin-17 inflammation to protumorigenic macrophage polarization in human hepatocellular carcinoma. Hepatology. 62:1779–1790. *Corresponding author.