Targeting B Cells to Tackle Immune System Suppression in High Risk Prostate Cancers

In mouse models immune cell manipulation plus chemotherapy achieves prostate cancer remission where chemotherapy alone fails

Blocking or removing immune-suppressing cells , researchers at the University of California, San Diego School of Medicine have found, allows a special type of chemotherapy — and the immune cells it activates — to destroy prostate tumors.

This combination therapy, termed chemoimmunotherapy, achieved near complete remission in mouse models of advanced prostate cancer.

Prostate cancer fails to respond to a type of immunotherapy drugs called checkpoint inhibitors. These drugs disable cancer cells’ "cloaking mechanism" so that a person’s own immune system can better fight the tumor.

According to the UC San Diego researchers, this specific resistance is likely due in part to immunosuppressive B cells, In men with prostate cancer, these cells are commoner in aggressive tumors and at advanced stages of disease.

In 2013 a team from The Scripps Research Institute showed that B cells can be forced to kill off parts of themselves in a process called selective apoptosis. Meanwhile the San Diego team, examining how B cells are imported into prostate cancer tumors, found that they are recruited by a chemical messenger (chemokine CXCL13) and promote the progression of castrate-resistant tumor cells by producing lymphotoxin.

Immunosuppressive B cells, as their name suggests, keep the immune system at bay, rendering most therapies ineffective and allowing malignant tumors to grow unchecked. These B cells are found in significant numbers in aggressive prostate tumors. In archived radical prostatectomy specimens, tissue samples from patients in a "high-risk group . . . and from those who eventually had PCa recurrence or progression ... did show significantly more intra-tumoral CD20+ B-cell staining" (Tumor infiltrating B-cells are increased in prostate cancer tissue, J Transl Med. 2014).

This latest UC San Diego study worked with three different mouse models of advanced prostate cancer. All three models were resistant to low doses of the chemotherapy drug oxaliplatin, which has the ability to activate cancer-killing immune cells.

When the researchers blocked the development or function of immunosuppressive B cells or removed them entirely before treating the mice with low-dose oxaliplatin, the prostate tumors were almost completely destroyed by the mice’s own immune cells. The team got similar results when low-dose oxaliplatin was combined with a checkpoint inhibitor.

“The presence of such B cells in human prostate cancer calls for clinical testing of this novel therapeutic approach,” said Shabnam Shalapour, PhD, postdoctoral researcher and first author of the study.

“In addition to prostate cancer, similar immunosuppressive B cells can be detected in other human cancers,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego. “This indicates that B cell-mediated immunosuppression might be the reason several other cancers are also unresponsive to checkpoint inhibitors, raising the hope that chemoimmunotherapy will have broader applications for many cancer types.”

Notes, Sources, and Related

Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy is published April 29 in Nature. Shabnam Shalapour, lead author, is a post doc in Tumor immunology at Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine and Department of Pathology, University of California San Diego (UCSD), USA.

A UCSD press release on which this article is based in part was written by Heather Buschman, PhD for UC San Diego News Center.

The prostate cancer connection:

Tumor infiltrating B-cells are increased in prostate cancer tissue J Transl Med. 2014; 12: 30.

Oxaliplatin's recent role in prostate cancer therapy

Oxaliplatin has a long history of use for colorectal cancer and is also used for ovarian cancer. Lately it has been shown to have some efficacy against aggressive castration-resistant (hormone-refractory) prostate cancer. See: Is there a role for platinum chemotherapy in the treatment of patients with hormone-refractory prostate cancer? Cancer. 2007 Feb 1;109(3):477-86.

New strategies against prostate cancer--Pt(II)-based chemotherapy. Curr Med Chem. 2012;19(27):4678-87.

Prostate cancer is the second leading cause of cancer-related death in American men. About one in seven men will be diagnosed with prostate cancer during their lifetimes.