Pancreatic cancer Spotlight on B cells

Nature Reviews Cancer | Research Highlight
Pancreatic cancer Spotlight on B cells

Sarah Seton-Rogers

Nature Reviews Cancer 16,67(2016)doi:10.1038/nrc.2016.7
Published online 29 January 2016

Three papers published in Cancer Discovery have shown that different subsets of B cells can promote development and progression of pancreatic ductal adenocarcinoma (PDAC).

Pylayeva-Gupta et al. detected B cell infiltrates and the B cell chemoattractant CXCL13 in human pancreatic intraepithelial neoplasia (PanIN) and in PanIN from LSL-KrasG12D;Ptf1a-Cre (hereafter KrasG12D) mice.

A CXCL13-blocking antibody prevented B cell infiltration in KrasG12D mice and in mice orthotopically injected with KrasG12D-expressing pancreatic ductal epithelial cells (PDECs); importantly, it also reduced the growth of orthotopic tumours.
KrasG12D PDECs implanted into mice lacking B cells (μMT mice) had reduced tumour growth compared with tumours grown in wild-type mice, and tumour growth was restored by adoptive transfer of B cells, indicating a direct role for B cells.
Furthermore, the CD19+CD1dhighCD5+ subpopulation of B cells was shown to be crucial for promoting tumour growth via production of interleukin 35 (IL-35), which seems to increase PDEC proliferation.

Lee et al. investigated the contribution of hypoxia-inducible factor 1α (HIF1α) to PDAC. PanINs in KrasG12D mice progress to invasive PDAC, and HIF1α expression and hypoxia were detected at all stages. However, KrasG12D mice with pancreas-specific deletion of HIF1α (KrasG12D;Hif1aKO mice) had increased PanIN and progression to PDAC. Interestingly, overall survival of the two mouse strains was similar, indicating that HIF1α might switch from a protective role to a tumour-promoting role during progression.

HIF1α deletion increased B cell infiltration in PanIN lesions, and human PanIN and PDAC samples also had increased levels of B cells. Examination of B cell subpopulations indicated that pancreata from KrasG12D mice had decreased numbers of B2 cells and increased numbers ofB1 cells compared with wild-type mice, and this ratio shifted further in KrasG12D;Hif1aKO mice. Depletion of B cells in both PDAC models reduced the number of higher grade PanIN lesions. Further experiments suggested that B cells are recruited to HIF1α-deficient tumours through increased expression of B cell chemoattractants, including CXCL13, through a non-tumour-cell-autonomous mechanism.

Gunderson, Kaneda et al. also found that PDACs had high B cell infiltration, as well as infiltration of Fcγ receptor (FcγR)-positive myeloid cells. The authors hypothesized that these two cell types might interact to promote tumorigenesis. PDACs derived from orthotopic implantation of LSL-KrasG12D;Pdx1-Cre cells (a PDAC model similar to LSL-KrasG12D;Ptf1a-Cre) that also lacked Trp53 or Cdkn2a in syngeneic mice had substantial infiltration of B cells, including B1 cells and several other B cell subpopulations. Implantation of these PDAC cells into mice lacking B cells (Igh-J−/− mice) resulted in smaller tumours compared with controls; a similar result was observed in FcγR-deficient mice, indicating that both B cells and myeloid cells are important for PDAC development.

The authors then investigated signalling pathways common to both B cells and macrophages (a subset of myeloid cells).
Activated Bruton's tyrosine kinase (BTK) was present in both B cells and macrophages inhuman and orthotopic mouse PDAC tumours.
Several lines of evidence suggested that the γ-isoform of PI3K (PI3Kγ) activates BTK in macrophages to promote production of immunosuppressive T helper 2 (TH2) cytokines. This TH2 polarization of macrophages occurred following co-culture with PDAC-derived B cells and was blocked by the BTK inhibitor ibrutinib, suggesting that B cells promote the pro-tumorigenic macrophage phenotype, and that BTK signalling is tumour promoting in both cell types.
Ibrutinib and a PI3Kγ inhibitor suppressed orthotopic PDAC growth; a combination of the two drugs had no additional effects. The inhibitors also reduced tumour size in late-stage tumours, which suggests possible therapeutic efficacy.

“B cells might contribute to PDAC progression in different ways”

Overall, these data suggest that B cells might contribute to PDAC progression in different ways, depending on the biological context.
Understanding the complete immune environment of these tumours and further dissecting the roles of B cells will be important for the development of effective immunotherapies for PDAC.

References

Pylayeva-Gupta, Y. et al. IL-35 producing B cells promote the development of pancreatic neoplasia. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-15-0843 (2015)
Lee, K. E. et al. Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-15-0822 (2015)
Gunderson, A. J., Kaneda, M. M. et al. Bruton's Tyrosine Kinase (BTK)-dependent immune cell crosstalk drives pancreas cancer. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-15-0827 (2015)