Increased B-cell ICOSL Expression Improves Chemotherapy Response

B lymphocytes in the tumor microenvironment (TME) may have antitumor or tumorigenic activities and may even switch from one role to the other. Using single-cell transcriptomic profiling of B cells from patient breast tumors before and after neoadjuvant chemotherapy, Lu, Zhao, Liao, and colleagues discovered that one B-cell population dramatically increased in abundance following chemotherapy. Specifically, cells expressing high levels of ICOLSG (encoding ICOSL) and CR2 along with low levels of IL10 expanded from 1% to greater than 45% of tumor-infiltrating B cells after chemotherapy. Further analysis revealed that the abundance of ICOSL⁺ B cells in the tumor immune infiltrate correlated with improved disease-free survival and overall survival in patients with breast cancer (excluding those with the HR⁺HER2⁻ subtype) receiving neoadjuvant chemotherapy. Experiments in three different mouse models demonstrated that, as in patients, ICOSL^hiCR2^hiIL10^lo B cells expanded following chemotherapy, and the presence of ICOSL⁺ B cells in the TME improved the immune response to chemotherapy. Mechanistically, ICOSL produced by tumor-infiltrating B cells appeared to act by increasing the prevalence of antitumor T cells in the TME, enhancing chemotherapy response. Additionally, complement activation via CR2 was required for the induction of ICOSL⁺ B cells in the TME following chemotherapy in mice, an effect also seen in in vitro and co-culture experiments using human cells. Notably, in the co-culture experiments. some breast cancer cell lines did not induce ICOSL⁺ B cells after chemotherapy, and further analysis revealed that these cell lines had higher expression of CD55, encoding a complement-inhibitory protein, than cell lines that did induce ICOSL⁺ B cells. Mouse experiments confirmed that tumor CD55 was linked to chemotherapy resistance caused by inhibition of complement activation–mediated ICOSL⁺ B-cell induction. In pretreatment patient tumors, higher levels of CD55 were associated with lower levels of ICOSL⁺ B-cell infiltration following treatment, greater resistance to neoadjuvant chemotherapy, and poorer clinical outcomes. In summary, this study elucidates a chemotherapy-induced switch in B-cell subtype associated with clinical outcome in breast cancer.

Lu Y, Zhao Q, Liao JY, Song E, Xia Q, Pan J, et al. Complement signals determine opposite effects of B cells in chemotherapy-induced immunity. Cell 2020 Mar 5 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.