B cells and tertiary lymphoid structures promote immunotherapy response

Helmink, B.A.; Reddy, S.M.; Gao, J.J.; Zhang, S.J.; Basar, R.; Thakur, R.; ... ; Wargo, J.A. (2020)

Article / Letter to editor

Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers(1-10) and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity(11-15), although these have been less well-studied in ICB treatment(16). A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling(17) that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter(18)) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

• All authors: Helmink, B.A.; Reddy, S.M.; Gao, J.J.; Zhang, S.J.; Basar, R.; Thakur, R.; Yizhak, K.; Sade-Feldman, M.; Blando, J.; Han, G.C.; Gopalakrishnan, V.; Xi, Y.X.; Zhao, H.; Amaria, R.N.; Tawbi, H.A.; Cogdill, A.P.; Liu, W.B.; LeBleu, V.S.; Kugeratski, F.G.; Patel, S.; Davies, M.A.; Hwu, P.; Lee, J.E.; Gershenwald, J.E.; Lucci, A.; Arora, R.; Woodman, S.; Keung, E.Z.; Gaudreau, P.O.; Reuben, A.; Spencer, C.N.; Burton, E.M.; Haydu, L.E.; Lazar, A.J.; Zapassodi, R.; Hudgens, C.W.; Ledesma, D.A.; Ong, S.; Bailey, M.; Warren, S.; Rao, D.; Krijgsman, O.; Rozeman, E.A.; Peeper, D.; Blank, C.U.; Schumacher, T.N.; Butterfield, L.H.; Zelazowska, M.A.; McBride, K.M.; Kalluri, R.; Allison, J.; Petitprez, F.; Fridman, W.H.; Sautes-Fridman, C.; Hacohen, N.; Rezvani, K.; Sharma, P.; Tetzlaff, M.T.; Wang, L.H.; Wargo, J.A.
• Date: 2020-01-15
• Journal: Nature
• Volume: 577
• Issue: 7791
• Pages: 549 - 555
• DOI: doi:10.1038/s41586-019-1922-8
• Link: https://www.nature.com/articles/s41586-019-1922-8