A Darwinian perspective on tumor immune evasion

Abstract

Evading immune-mediated destruction is a critical step of tumor evolution and the immune system is one of the strongest selective pressures during tumorigenesis. Analyzing tumor immune evasion from a Darwinian perspective may provide critical insight into the mechanisms of primary immune escape and acquired resistance to immunotherapy. Here, we review the steps required to mount an anti-tumor immune response, describe how each of these steps is disrupted during tumorigenesis, list therapeutic strategies to restore anti-tumor immunity, and discuss each mechanism of immune and therapeutic evasion from a Darwinian perspective.

Keywords: Breast cancer; Immune evasion; Tumor evolution.

Figure 1.. Schematics of immunoediting.

In the elimination phase, most malignant cells are sensitive to anti-tumor immunity and immunity steps are intact. The elimination of immune-sensitive cells selects for cells with perturbed immunity steps that are no longer sensitive to immune-mediated elimination. There is an evolutionary bottleneck that selects for cells that are either able to evade anti-tumor immunity or can proliferate quickly enough to sustain a high turnover, immune sensitive population. In the equilibrium phase, there is a mixture of immune-sensitive and insensitive cells and tumor cell elimination is proportional to rates of cell proliferation, leading to no net tumor outgrowth. Intact and perturbed immunity steps are both represented during this phase. For tumor outgrowth to occur, immune-insensitive cells are selected for during a second evolutionary bottleneck, allowing for tumor cell proliferation to occur without elimination by anti-tumor immunity. In the escape phase, most malignant cells are insensitive to anti-tumor immunity and immunity steps are perturbed. It is possible for immune-sensitive subclones with intact immunity steps to emerge and/or remain within this population if escaped clones maintain an immunosuppressive environment, thus shielding the sensitive clone from anti-tumor immunity.

Figure 2.. Steps of immune recognition and escape.

A, Requirements, escape mechanisms, and restoration options of immune identification. The successful identification of malignant cells requires cancer cell antigen expression, followed by antigen uptake by APCs. At each requirement, there is an opportunity for immune escape via the mechanisms listed. Possible methods of therapeutic restoration are shown and therapeutic success would allow for identification to continue. B, Requirements, escape mechanisms and restoration options of activation. Optimal activation of T cells requires an APC-mediated effector state transition, CD4+ T cell-mediated help, and avoidance of inhibition/exhaustion. At each requirement, there is an opportunity for immune escape via the mechanisms listed. Possible methods of therapeutic restoration are shown, and therapeutic success would allow for activation to continue. C, Requirements, escape mechanisms and restoration options of targeting. Successful targeting of immune cells to tumors requires appropriate tumor homing, followed by tumor infiltration. At each requirement, there is an opportunity for immune escape via the mechanisms listed. Possible methods of therapeutic restoration are shown, and therapeutic success would allow for targeting to continue. D, Requirements, escape mechanisms and restoration options of elimination. CTL-mediated cancer cell elimination requires antigen presentation and recognition, target cell binding, and effector molecule delivery and function. At each requirement, there is an opportunity for immune escape via the mechanisms listed. Possible methods of therapeutic restoration are shown, and therapeutic success would allow for elimination to continue.

Figure 3.. Multiple escape mechanisms at each immunity step provide an opportunity for immune escape and selection of an immune-evasive tumor.

An immune-sensitive tumor contains intact immunity steps. At each step there are multiple opportunities for immune escape to occur, selecting for immune evasive cells. Elimination of immune-sensitive clones selects for cells with a variety of immune evasive properties. These cells are free to expand into immunologically heterogeneous, clinically detectable lesions. The diversity of immune escape mechanisms represented in this tumor reveals how immunotherapeutic approaches targeting only one mechanism of immune escape will select for clones with alternative escape mechanisms. Thus, a small biopsy may not reveal the heterogeneity of immune escape mechanisms present within a tumor.