Cell-Cell Communication in the Tumor Microenvironment

Peter P. Ruvolo, PhD, assistant professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center in Houston, investigates the role of microenvironments in cancer and treatment resistance. Cancer Network asked him about the roles of the cancer microenvironment and cellular signals in immune evasion and biology.

Cancer Network: What are some of the ways cancer cells and cells in their microenvironment communicate to facilitate immune evasion, progression, and drug resistance?

Dr. Ruvolo: Communication between cancer cells and the cells in the microenvironment is a two-way process that involves a wide variety of non-cancer cells and a diverse range of mechanisms. Non-cancer microenvironment cells include stromal cells which can be mesenchymal stem cells (MSC) and their derivatives, including osteoblastic cells and adipocytic cells, cancer-associated macrophages and fibroblasts, and a wide variety of immune and inflammatory cells.

To be brief, let’s talk about MSC, which participate in many mechanisms in both solid tumors and blood cancers. They produce a wide variety of secreted proteins that can suppress immune surveillance, such as TGF-β, galectins, and various interleukin molecules. They can also produce cytokines and chemokines that can support cell growth and survival of the cancer cell. When a leukemia cell comes in contact with a MSC, cell adhesion promotes production of many survival molecules including anti-apoptotic BCL2 (B-cell lymphoma 2) family molecules in the leukemia cell. The mechanism can involve integrin-mediated signaling.

The cancer cell can also influence the microenvironment cells to promote pathways that benefit the cancer cell. The cancer cell can suppress immune cells by utilizing checkpoint inhibitor molecules such as PD-L1 (programmed death-ligand 1) or CTLA4. It is also possible that the cancer cell promotes changes in the non-immune microenvironment cells such as MSC to also express checkpoint inhibitor molecules.

We have found in proteomic analysis of MSC derived from AML (acute myeloid leukemia) patients compared to MSC derived from healthy donor that at least one immunosuppressive molecule (Galectin 3) is elevated in AML MSC and high Galectin 3 in AML MSC was associated with relapse. Whether immune suppression is at work in that case is not clear but this question is worth pursuing.

Cancer Network: You have said that cancer cells are really quite “fragile” outside of their protective microenvironmental niche. What is an example of that fragility? 

Dr. Ruvolo: In the absence of support cells, leukemia cells removed from a patient will quickly die. Even when a cocktail of cytokines is provided, the leukemia cells do not grow. The reason patient-derived xenograft models are so important is that they enable the investigator to grow primary leukemia cells with the aid of a host microenvironment- though there are the drawbacks that the host is a different species and the mice used are immune-incompetent. Researchers are working on developing “humanized” mice to overcome this problem.

Cancer Network: Emerging targets in the interplay between microenvironment and cancer cells include protein tyrosine phosphatases. How do aberrations in protein tyrosine phosphatase illustrate the ways support cells in cancer microenvironments can help drive cancer progression? 

Dr. Ruvolo: The PTPN11 story in Noonan Syndrome is a very interesting example of how the microenvironment can drive cancer development. Mutation of PTPN11 in stromal cells induces transformation of normal blood stem cells to become leukemic. It is thought that this occurs via changes in RAS which is regulated by PTPN11 and is a potent oncogene. How the PTPN11-mutant stromal cell promotes leukemogenesis is not clear, though a cytokine-based mechanism has been suggested.

Cancer Network: How has single-cell sequencing affected our understanding of cancer evolution and cancer microenvironments?

Dr. Ruvolo: Advances in single-cell technology have been critical to our understanding of how cancers evolve. In acute myeloid leukemia, single-cell sequencing has shown that there are usually heterogenous populations of malignant cells in a single patient and these populations can change in response to therapy.

Single-cell technologies will help us determine if in particular patients the transformation event involved a single cell or whether more than one initiating cancer cell is involved. Single-cell sequencing will also be useful to gauge the impact the microenvironment has on cancer cells that prove to be most resistant to therapy.

Cancer Network: How can understanding the cancer microenvironment contribute to the development of new cancer treatment strategies?

Dr. Ruvolo: An understanding of the contribution of the various components of the tumor microenvironment will allow us to one day truly tailor therapy for each patient.

The success of the immune checkpoint inhibitors in many cancers is an excellent example of how addressing a microenvironment-mediated resistance mechanism can be beneficial for the patient. Another very promising immune therapy approach involves the development of immune cells that are engineered to target proteins that are present on cancer cells. CAR T-cells and also CAR NK [natural killer] cells are being developed to target a number of different cancer antigens and many of the clinical trials have been very promising.

However, as these engineered T cells will still be subject to suppression by microenvironment factors, it will be necessary to address such mechanisms to optimize the efficacy of these novel agents. As the microenvironment also provides a safe haven for many cancer cells, strategies to mobilize cells from the tumor niche will render the malignant cells more sensitive to therapy. In the case of leukemia, mobilizing the malignant cells from the bone marrow will hopefully allow the bone marrow to resume its normal role in supporting hematopoiesis.