27 Apr 2013

Research into Cancer–Immune System Interactions

Immune cells can infiltrate the cancer microenvironment, the consequences of which are not well understood. The multi-faceted immune presence interacts with cancer cells in inhibitory and/or stimulatory ways, resulting in complex cancer–immune interactions. Below we describe our current mathematical and computational approaches to understand the consequences and implications of these intercellular interactions.

Tumor-Promoting Inflammation

The presence of cancer within a host initiates a systemic immune response towards the transformed cells. Inflammatory immune cells such as neutrophils, platelets, macrophages, and natural killer cells, are recruited to the tumor site where they initiate the wound healing process. Tumors, sometimes viewed as wounds that never heal, can be promoted by these inflammatory actions.  Once the adaptive immune response is activated by dendritic cells and macrophages, CD8+ T cells, or
cytotoxic T lymphocytes, infiltrate the tumor and induce apoptosis in the target tumor cells. Depending on the cytokines and other signals present in the tumor microenvironment, recruited immune cells will either form a pro-tumor immunity (typified by cytokines such as TGF-β, IL-6, and IL-10 and cells such as M2 macrophages, Th-2 T helper cells, and myeloid derived suppressor cells) or an anti-tumor immunity (typified by cytokines such as IFN-γ, IL-2, and IL-12 and cells such as M1 macrophages, Th-1 T helper cells, and cytotoxic lymphocytes).

To investigate the role of tumor-promoting inflammation, an emerging hallmark of cancer, we have developed a mathematical model for cancer-immune interactions that can capture both the pro-angiogenic, tumor-progressing actions of a pro-tumor inflammatory microenvironment, and the anti-angiogenic, tumor-inhibiting actions of an anti-tumor inflammatory microenvironment. This model utilizes principles of generalized logistic growth, which captures some of the inherent variability underlying tumor growth in an immune competent host that is often neglected in macroscopic measurements and in mathematical models. From model simulations, the two types of inflammation (pro-tumor or anti-tumor) resolve into two fundamentally different classes of outcomes, where inflammation-enhanced tumor progression must either result in a decreased tumor burden, as in the anti-tumor case, or in an increased tumor burden, as in the pro-tumor case. These results suggest that, in some cases, fast tumor growth may be advantageous, if it leads to a significantly smaller tumor burden. In such cases, it is possible that treatments should be targeted towards enhancing the stability of an anti-tumor inflammatory environment instead of towards immediate tumor regression.

Tumor Immunoevasion

Despite highly evolved adaptive immune responses, tumors often manage to escape recognition by the immune system. This process is known as immunoevasion, and is another emerging hallmark of cancer.

When hematopoietic stem cells leave the bone marrow they differentiate into either lymphoid progenitors or myeloid progenitors. Lymphoid progenitors migrate to the thymus where they differentiate into T, B, and NKT cells. Myeloid progenitors differentiate into monocytes, migrate to tissues, and differentiate into myeloid cells such as dendritic cells (DCs) and macrophages. When an immature DC encounters an antigen, it internalizes the antigen to display fragments on its membrane. The DC then matures as it migrates to a lymph node. Maturation involves the loss of ability to engulf pathogens and an increased ability to communicate with T cells. Within the lymph nodes (collection points where antigen presenting cells interact with T cells attracted to the node via chemotaxis), mature DCs activate naïve T cells to develop a specific immune response. Activated cytotoxic T cells undergo rapid clonal expansion and migrate throughout the body in search of relevant targets. T cells perform their cytotoxic function by inducing apoptosis in the target cell through the secretion of perforin and granzymes or through Fas/Fas-ligand binding.

Within the process of activating the adaptive immune response described above, two significant functions may be subverted by tumors: antigen presentation (maturation of DCs) and T cell functionality.

Antigen presentation suppression

If antigen presentation is blocked then naïve T cells are not activated and a specific immune response is not mounted. A number of cytokines, chemokines and growth factors, such as HIF-1α, VEGF, nitric oxide, and reactive oxygen species (ROS), produced within the tumor microenvironment may interfere with the process of DC maturation. Without DC maturation, there may be an accumulation of immunosuppressive factors, such as myeloid derived suppressor cells (MDSCs), in the tumor microenvironment resulting in immunoevasion.

In order to investigate this process from a modeling perspective, we formulated a system of ordinary differential equations in a predator-prey type system, where the prey (cancer cells) have a defense mechanism (immunoevasion) against recognition by the predator (immune system). Our analysis suggests that this mechanism can have significant effects on overall tumor-immune dynamics, ultimately allowing for either tumor suppression or tumor escape in a manner that depends on the strength of the immune suppression [Kareva et al, 2010]. Currently, we are investigating the possible role of glycolysis and the resulting reduction of pH in a hypoxic tumor microenvironment as another possible mechanism for immune evasion.

Impaired T cell functionality and immune resistance

The immune response poses a second barrier to tumor growth after the angiogenic switch. Immune surveillance of tissues allows for early detection of transformed cells. If these transformed cells are not recognized as “self”, they are eliminated by the immune system. Through repeated exposure of the transformed cells to this immune selection process, various phenotypes can arise within the cancer cell population, creating a heterogeneous population of neoplastic cells. These immunoedited cells may develop the ability to evade the immune response and grow in an uncontrolled manner.

After prolonged periods of immune-induced dormancy, T cells can lose effectiveness in their cytotoxicity. This loss may be due to either T cell tolerization to the cancer cells or to an increased cancer cell resistance to immune attack. Both of these mechanisms are intertwined in the process of immunoediting that can lead to tumor escape from immune control.

To investigate the heterogeneous population-level dynamics involved in this immune selection process, we are working on a mathematical model that can capture the essential cancer-immune interactions that may lead to T cell tolerization and / or the accumulation of immune-resistance by cancer cells. These two fundamentally different mechanisms of immune evasion would require specifically targeted therapies, which could be analyzed theoretically with this mathematical model.

Cancer Stem Cells and Immune System-Modulated Tumor Progression

The role of the immune system in tumor progression has been subject to discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression.

Without an immune response, a heterogeneous tumor population comprised of cancer stem cells and non-stem progenitors grows as conglomerates of self-metastases [Enderling etal., 2009]. This morphological phenomenon results from the interplay of cell proliferation, cell migration and cell death. With increasing cell death intra-tumoral spatial inhibitions are loosened, which in turn enable cancer stem cell cycling and thus, counter-intuitively, tumor progression [Enderlinget al., 2009b]. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. Focusing only on the cytotoxic function of the immune system, we were able to observe all immunoediting roles of the immune system: immune promotion at weak immune responses, immunoinhibition at strong immune responses, and immunoselection at all levels. Simulations of our model support a hypothesis previously put forward by Prehn [Prehn, 1972] that comparable tumor sizes can be observed for weak and strong immune reactions. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response.

Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step “immunoediting” concept — the modulation of tumor growth through inhibition, selection, and promotion. We propose more generally that a stem-cell-expansive influence may take the form of anything that encourages morphological fingering. Beyond immune response, this could include cell death, or even growth within restricted thin channels, as might be expected e.g. during invasion of host tissue.see more......

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