Prostate cancer bone metastases thwart immunotherapy by producing TGF-β

November 14, 2019

HOUSTON -- Prostate cancer that spreads to the bone triggers the destruction of bone tissue that, in turn, thwarts the effectiveness of immune checkpoint inhibitors by blocking the development of T cells that are crucial to successful treatment, researchers from The University of Texas MD Anderson Cancer Center report in Cell.

The discoveries by a team led by Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at MD Anderson, explain why immunotherapy has been largely unsuccessful against prostate cancer bone metastases and point to a possible combination that could reverse the resistance.

Their findings also highlight the need to look at metastatic cancer in a different light.

"We tend to think of stage 4 disease as being uniform, but it's not all the same," Sharma says. "We need to be more thoughtful about the immune microenvironment in different areas of metastasis to take into account different immune responses in those microenvironments when we develop treatments."

Research points to anti-TGF-β, anti-CTLA-4 combination

The team found that the bone destruction caused by tumors leads to massive production of transformational growth factor-beta (TGF-β), a protein that causes helper T cells to polarize into Th17 CD4 cells instead of the Th1 CD4 effector cells required to trigger an anti-tumor immune response.

Combining anti-TGF-β treatment with an inhibitor of the CTLA-4 checkpoint on T cells stifled growth of bone metastases in a mouse model. "We're working to develop a combination clinical trial of anti-CTLA-4 and anti- TGF-β for metastatic prostate cancer," Sharma says.

A majority of men with prostate cancer have their cancer progress to metastatic castration-resistant disease, which is almost uniformly lethal. About 70-80% of men with stage 4 prostate cancer develop bone metastases. While recent research by Sharma and colleagues showed that a combination of anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) checkpoint inhibitors helps some men with stage 4 prostate cancer, it largely failed against bone metastasis.

To understand this issue, Sharma's team first examined pre- and post-treatment bone marrow from patients for clues about treatment resistance. They further explored their observations in mouse models of metastatic prostate cancer and tested combination therapies - "reverse translation" of their findings from people.

Absence of Th1 CD4 T cells

When it works, immune checkpoint blockade expands Th1 CD4 effector cells, which leads to activation of killer CD8 T cells and generation of long-term memory cells.

The team found plenty of Th1 effectors in the soft tissues of patients treated with ipilimumab, but these crucial cells were largely absent in the bones, where they instead found abundant Th17 cells.

"The important point here is the absence of the Th1 cells," Sharma notes. Cytokines polarize helper cells to different types, and in the bone microenvironment they produce an abundance of Th17 cells. The function of the Th17 cells there is not known.

The team developed two mouse models of metastatic disease - one that represented bone metastases and a subcutaneous model that represented primary prostate cancer or soft-tissue metastases.

As in humans, treatment with ipilimumab and nivolumab combination shrank tumors and extended survival of the mice with soft-tissue metastases but had minimal effects on the tumors and survival of those with bone metastases.

Treatment expanded tumor infiltrating CD4 and CD8 T cells in both soft tissue and bones, but failed to inhibit growth of bone tumors. Mass cytometry analysis of the T cells showed why. The CD4 T cells in the bone tumors were only of the Th17 and regulatory T cell (Treg) lineages. Tregs inhibit immune response. There were no Th1 effector cells.

In the subcutaneous model, Th1 effectors were detected before treatment and then greatly increased after treatment while Th17 and Tregs decreased.

TGF-β protects bone tumors

Lack of Th1 cells in the bone marrow suggested a distinct cytokine profile in the bone microenvironment. The team analyzed levels of 13 cytokines in the tumor-bearing and tumor-free femurs of the mice.

They found significant elevation of TGF-β, known to restrain Th1 lineage and drive both Th17 and Treg development. Th17 also requires the presence of Interleukin-6, which was found abundantly, as expected, in the bone marrow.

Bone metastasis triggers abnormal bone remodeling, and bone components are known as a major reservoir of TGF-β. The team hypothesized that bone matrix remodeling causes the high TGF-β levels in prostate bone metastases.

Their experiments confirmed that osteoclasts - cells that degrade bone - activated by tumors release excessive amounts of TGF-β while they erode bone surfaces.

To test the hypothesis in humans, they compared TGF-β levels in the bone marrow of healthy donors and prostate cancer patients with and without bone metastases. There was no difference in TGF-β levels between healthy controls and patients without bone metastases, while patients with bone tumors had aberrantly high levels of TGF-β in their bones.

Blocking TGF-β restores Th1 cells and boosts immunotherapy

Treating mice with bone metastases with the ipilimumab and nivolumab combination failed to stop tumor growth. But adding anti- TGF-β to the immunotherapy combination halted tumor growth.

Anti- TGF-β and ipilimumab alone also stifled bone metastasis growth. This combination also increased the frequency of Th1 cells and decreased Tregs in the bone microenvironment.
Co-authors with Sharma are first author Shiping Jiao, a graduate student at The University of Texas MD Anderson/UTHealth Graduate School of Biomedical Sciences, Sumit Subudhi, M.D., Ph.D., Ana Aparicio, M.D., Baoxiang Guan, and Yuji Miura, M.D., of Genitourinary Medical Oncology; and Zhongqi Ge, Ph.D., of Immunology.

This research was supported by MD Anderson's Immunotherapy Platform, part of its Moon Shots Program, a collaborative effort to rapidly develop scientific discoveries into meaningful clinical advances that save patients' lives, and by the Parker Institute for Cancer Immunotherapy. Sharma is co-director of the Parker Institute for Cancer Immunotherapy at MD Anderson.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institution's sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 49 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No.1 for cancer care in U.S. News & World Report's "Best Hospitals" survey. It has ranked as one of the nation's top two hospitals for cancer care since the survey began in 1990, and has ranked first 14 times in the last 17 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

University of Texas M. D. Anderson Cancer Center

Related Prostate Cancer Articles from Brightsurf:

Low risk of cancer spread on active surveillance for early prostate cancer
Men undergoing active surveillance for prostate cancer have very low rates - one percent or less - of cancer spread (metastases) or death from prostate cancer, according to a recent study published in the Journal of Urology®, an Official Journal of the American Urological Association (AUA).

ESMO 2020: Breast cancer drug set to transform prostate cancer treatment
A drug used to treat breast and ovarian cancer can extend the lives of some men with prostate cancer and should become a new standard treatment for the disease, concludes a major trial which is set to change clinical practice.

Major trial shows breast cancer drug can hit prostate cancer Achilles heel
A drug already licensed for the treatment of breast and ovarian cancers is more effective than targeted hormone therapy at keeping cancer in check in some men with advanced prostate cancer, a major clinical trial reports.

The Lancet: Prostate cancer study finds molecular imaging could transform management of patients with aggressive cancer
Results from a randomised controlled trial involving 300 prostate cancer patients find that a molecular imaging technique is more accurate than conventional medical imaging and recommends the scans be introduced into routine clinical practice.

Common genetic defect in prostate cancer inspires path to new anti-cancer drugs
Researchers found that, in prostate cancer, a mutation leading to the loss of one allele of a tumor suppressor gene known as PPP2R2A is enough to worsen a tumor caused by other mutations.

First prostate cancer therapy to target genes delays cancer progression
For the first time, prostate cancer has been treated based on the genetic makeup of the cancer, resulting in delayed disease progression, delayed time to pain progression, and potentially extending lives in patients with advanced, metastatic prostate cancer, reports a large phase 3 trial.

Men taking medications for enlarged prostate face delays in prostate cancer diagnosis
University of California San Diego School of Medicine researchers report that men treated with medications for benign prostatic hyperplasia (enlarged prostate) experienced a two-year delay in diagnosis of their prostate cancer and were twice as likely to have advanced disease upon diagnosis.

CNIO researchers confirm links between aggressive prostate cancer and hereditary breast cancer
The study has potential implications for families with members suffering from these types of tumours who are at an increased risk of developing cancer.

Distinguishing fatal prostate cancer from 'manageable' cancer now possible
Scientists at the University of York have found a way of distinguishing between fatal prostate cancer and manageable cancer, which could reduce unnecessary surgeries and radiotherapy.

Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.

Read More: Prostate Cancer News and Prostate Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to