Abstract
While the cellular origin of lymphoma is often characterized by chromosomal translocations and other genetic aberrations, its growth and development into a malignant neoplasm is highly dependent upon its ability to escape natural host defenses. Neoplastic cells interact with a variety of non-malignant cells in the tumor milieu to create an immunosuppressive microenvironment. The resulting functional impairment and dysregulation of tumor-associated immune cells not only allows for passive growth of the malignancy but may even provide active growth signals upon which the tumor subsequently becomes dependent. In the past decade, the success of immune checkpoint blockade and adoptive cell transfer for relapsed or refractory lymphomas has validated immunotherapy as a possible treatment cornerstone. Here, we review the mechanisms by which lymphomas have been found to evade and even reprogram the immune system, including alterations in surface molecules, recruitment of immunosuppressive subpopulations, and secretion of anti-inflammatory factors. A fundamental understanding of the immune evasion strategies utilized by lymphomas may lead to better prognostic markers and guide the development of targeted interventions that are both safer and more effective than current standards of care.
Highlights
Advances in the past decade have compelled cancer biologists to modify the underlying classical principles previously used to define the pathogenesis of cancer, such as sustained proliferative signaling and insensitivity to growth suppressors [1]
The most successful example to date of translating immune evasion strategies into anti-cancer therapies is the blockade of T cell checkpoint molecules like CTLA-4 or PD-1
Ex vivo studies of NHL patient samples revealed that direct cell contact with tumor cells induced differentiation of autologous PBMCs into CD4+CD25+FoxP3+ Tregs that were found to be directly responsible for effector T cell hyporesponsiveness by in vitro depletion experiments [73,78]
Summary
Advances in the past decade have compelled cancer biologists to modify the underlying classical principles previously used to define the pathogenesis of cancer, such as sustained proliferative signaling and insensitivity to growth suppressors [1] One such emerging hallmark of cancer is its ability to evade destruction by the immune system [2]. There is significant evidence showing that both innate and adaptive immunity play crucial roles in eliminating nascent transformed cells [3] These same protective mechanisms apply a selective pressure to shape the inherent immunogenicity of the developing tumor. Often originating from genetic alterations that bring an oncogene under the control of an Ig locus during physiological remodeling of the immunoglobulin genes, are no different [7] If these precancerous cells overcome intrinsic tumor suppression mechanisms, they are frequently recognized and eliminated by the immune system, a process called “immune surveillance” [8]. We discuss these immune evasion strategies, including molecules expressed at the surface of the cell, soluble factors that are secreted by the tumor, and cellular constituents that are recruited to maintain an immunosuppressive microenvironment
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