Leading the Way in Life Science Technologies

GEN Exclusives

More »

GEN Exclusives

More »
April 10, 2017

Solid Advances in Tumor Microenvironment Research

Efforts to Clean Up Solid Tumor Corruption Are Starting to Focus on Underlings, not Just Kingpins

Solid Advances in Tumor Microenvironment Research

In the lab, engineered T cells can kill ovarian cancer cells, whether they are from humans or, as shown by the illuminated proteins in this image, mice. Such killing action is to be extended to solid tumors. [Anderson and Stromnes/Greenberg Lab]

  • A tumor is half insane asylum, half construction site—a place where cancerous cells cooperate with ostensibly normal cells. When these disparate cell types work together, they violate conventional building codes, make use of the resources at hand, and accomplish what neither could alone—a travesty of normal, healthy tissue.

    Travesty tissue grows the way a building would grow, were it to combine poor architecture and an unlimited budget. As extensions are added, interior regions become increasingly inaccessible. Plumbing starts to leak. And passageways, all but impassable to emergency services, seem designed to outrage the fire marshal.

    Despite these flaws, travesty tissue remains a lively hub for the receipt of materials and the posting of packages. Construction never ceases, and the strange building practices pioneered at the tumor site start to overtake sound maintenance practices long observed at the properties down the road.

    This is the tumor microenvironment. It's less the work of cellular vandals, and more the product of mismanaged industry. It is, alas, an industry that specializes in amassing a diverse constituency, a network of win-win relationships that increasingly has its way until it brings about the ultimate lose-lose, which is to say, systemic collapse.

    The idea that the tumor microenvironment can be a cooperative enterprise is something relatively new, particularly in the context of metastasis. For over a century, metastasis has been characterized as a “seed and soil” process. Cancer “seeds,” shed primary tumors, travel through the bloodstream so that they may find fertile “soil” in distant tissues. Yet, fertile soil isn’t always ready and waiting. Sometimes, soil needs to be prepared. And soil preparation, like the formation of a primary tumor, may involve a degree of give and take.

  • A Shift in Emphasis

    The collaborative processes that sustain tumors and drive metastasis are of intensifying research interest, as evidenced by the presentations at the recent AACR event in Washington, DC. Collectively, these presentations stitched together continuous models of the tumor microenvironment. They showed how diverse constituents of the tumor microenvironment—cancer cells, stromal cells, immune cells, extracellular matrix, and molecular factors—interact to support cancer growth and progression. What’s more, the presentations also emphasized how a deeper understanding of the tumor microenvironment could suggest new anticancer strategies.

    For example, therapies that target a tumor’s supporting cells could be more effective than therapies that target cancer cells, given that supporting cells tend to be more genomically stable, and hence less likely to evolve resistance. Another possibility is combining adoptive cell therapy with vascular renormalization. Too often, immune cells engineered to attack cancer cells may be unable to navigate the eccentric vasculature in the tumor microenvironment. If, however, the vasculature could be improved, the immune cells would have a better chance of finding and eradicating their targets.

    In general, the AACR presenters approached the tumor microenvironment as though they were census takers. They are cataloguing all the elements of the tumor microenvironment—resident and infiltrating cells, patterns of gene expression, and intracellular and extracellular factors—while looking for opportunities to disrupt tumor progression and metastasis.

  • From Cancers of the Blood to Solid Tumors

    In one AACR presentation, Fred Hutchinson Cancer Research Center immunotherapy researcher Kristin Anderson, Ph.D., described how she, Philip Greenberg, M.D., and colleagues are working on ways to tweak their early successes with T-cell therapy for leukemia to apply to solid tumors. Although blood cancers have shown some vulnerability to T-cell therapies, solid tumors (like breast, lung, ovarian, and pancreatic cancers) are proving more resistant to this new wave of cancer therapies.

    The Fred Hutch team has identified proteins overproduced by ovarian cancer cells, known as WT1 and mesothelin, and have found that T cells engineered to specifically recognize these proteins can kill both human and mouse ovarian cancer cells in the lab. The team has also found that the T cells significantly extend survival in a mouse model of the cancer, but more work is needed to ready this therapy for clinical trials. "Tumor microenvironment issues,” said Dr. Anderson, come hand-in-hand with working on solid tumors."

    As a Fred Hutch release indicated, Dr. Anderson's presentation, entitled "Engineering adoptive T-cell therapy for efficacy in ovarian cancer," described three types of roadblocks to an effective ovarian cancer T-cell therapy—and how they are being overcome.

    • Immunosuppressive cells and proteins in the microenvironment that can signal the engineered T cells to shut down or ignore tumors. Existing checkpoint inhibitor drugs could circumvent this problem, Dr. Anderson said, and the Fred Hutch team is also exploring engineering the therapeutic T cells to block those immunosuppressive signals.
    • A "death signal" produced by both ovarian tumor cells and nearby blood vessels on their surfaces. This molecular signal causes T cells coming to the tumor from the bloodstream to commit suicide before they can fight the cancer. Shannon Oda, Ph.D., in the Greenberg lab is working on a new type of fusion protein that the engineered T cells will carry that will rewire their internal circuitry, causing the death signal to instead boost their anti-tumor activity.
    • The tumors' low-sugar environment. Fast-growing ovarian cancer cells churn through the glucose in their environment—the same energy source engineered T cells need to do their work. Researchers in the Greenberg lab are working to re-engineer the therapeutic T cells to process other sources of energy.

    Although her current work focuses on ovarian cancer, a particularly difficult-to-treat solid tumor, Dr. Anderson hopes the work will shed light on new therapeutic avenues for other solid tumors as well.

    "If we can solve some of the issues that really plague us with these hard ones,” she said, “then we can more readily apply them to some of the cancers that have fewer of these hurdles."

  • Immune Cells Gone Wrong

    In a talk provocatively titled “Macrophages—Evildoers in Cancer,” Jeffrey W. Pollard, Ph.D., of the MRC Centre for Reproductive Health at the University of Edinburgh, described how tumor evolution to malignancy requires manipulation of its tissue microenvironment. This is particularly true, he noted, for the immune infiltrate that is biased away from responding to the tumor to effect control and instead actively promotes progression.

    “The tumor immune response thus downregulates cytotoxic T-cell responses and promotes tissue repair and morphogenic activities of the infiltrating immune cells,” Dr. Pollard indicated in his abstract. “Thus, the environment tends to be dominated by innate immune cells, particularly macrophages and neutrophils, while cytotoxic T cells are often excluded.”

    Dr. Pollard’s group has been interested in macrophages. In many different mouse models of cancer, these immune cells have been shown to promote tumor progression and enhance metastasis. “In fact,” he emphasized, “macrophages appear to be involved in every step of tumor progression. They stimulate tumor initiation, enhance angiogenesis, promote tumor cell migration and intravasation, increase stem cell viability, suppress immune responses, and, at the metastatic site, promote extravasation and persistent growth.”

    Macrophage ablation, Dr. Pollard’s team has observed, results in inhibition of tumor progression and metastasis. It has also found that macrophage biologic activities are induced through a dynamic interplay with tumor cells that often involves reciprocal signaling.

    Dr. Pollard’s group has been particularly interested in the involvement of macrophages in enhancing metastasis, since it is metastatic disease that is responsible for most cancer deaths. The group, stated Dr. Pollard, has demonstrated a chemokine-signaling cascade that results in the recruitment of the progenitor monocytes and their retention in the tissue. This results, he continued, in differentiation of what we have termed metastasis-associated macrophages (MAMs).

    “MAMs confer survival signals and growth advantage to metastatic cells,” elaborated Dr. Pollard. “The MAMs, in turn, respond to local signals to upregulate an inflammatory gene signature through the tyrosine kinase transmembrane receptors, vascular endothelial growth factor receptor 1 (VEGFR1 or FLT1) and colony stimulating factor 1 receptor (CSF1R). Furthermore, monocytes appear to be preadapted by the primary tumor to promote metastasis by the generation of preferred sites known as premetastatic niches. Thus, understanding monocyte biology, the mechanisms of their recruitment, and differentiation is of central importance to the fundamental appreciation of the role of macrophages in the tumor.”

Related content