Signaling defects in anti‐tumor T cells

Abstract

The immune response to cancer has been long recognized, including both innate and adaptive responses, showing that the immune system can recognize protein products of genetic and epigenetic changes in transformed cells. The accumulation of antigen-specific T cells within the tumor, the draining lymph node, and the circulation, either in newly diagnosed patients or resultant from experimental immunotherapy, proves that tumors produce antigens and that priming occurs. Unfortunately, just as obviously, tumors grow, implying that anti-tumor immune responses are either not sufficiently vigorous to eliminate the cancer or that anti-tumor immunity is suppressed. Both possibilities are supported by current data. In experimental animal models of cancer and also in patients, systemic immunity is usually not dramatically suppressed, because tumor-bearing animals and patients develop T-cell-dependent immune responses to microbes and to either model antigens or experimental cancer vaccines. However, inhibition of specific anti-tumor immunity is common, and several possible explanations of tolerance to tumor antigens or tumor-induced immunesuppression have been proposed. Inhibition of effective anti-tumor immunity results from the tumor or the host response to tumor growth, inhibiting the activation, differentiation, or function of anti-tumor immune cells. As a consequence, anti-tumor T cells cannot respond productively to developmental, targeting, or activation cues. While able to enhance the number and phenotype of anti-tumor T cells, the modest success of immunotherapy has shown the necessity to attempt to reverse tolerance in anti-tumor T cells, and the vanguard of experimental therapy now focuses on vaccination in combination with blockade of immunosuppressive mechanisms. This review discusses several potential mechanisms by which anti-tumor T cells may be inhibited in function.

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

“…While many studies have improved our understanding of tumor initiation and progression, many questions regarding the phenomenon of an increasingly ineffective tumor immune response during tumor growth are in need of elucidation [5,6] . In fact, during cancer progression colorectal tumor cells acquire various characteristics that allow them to evade immunological surveillance [7][8][9] .…”

Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

“…Because ganglioside inhibition of immune cell function is often reversible, inhibition of lytic activity in CTL by shed gangliosides might be reversed by removal of CTL from the tumor ganglioside-rich tumor microenvironment. This would provide an explanation for the rapid recovery of tumor-specific cytotoxic activity of CD8 + tumor-infiltrating lymphocytes upon in vitro culture after isolation from the tumor mass (3,42).…”

“…Lytic activity of CD8 + CTL has been shown to be defective in various mouse tumor models and in human cancer (3). Soluble factors generated as a result of tumor growth (i.e., produced by tumor and/or by host [immune] cells) have been proposed to have an important role in inhibiting CD8 + T cell lytic function.…”

Shaping of NK Cell Responses by the Tumor Microenvironment

“…For instance, it was shown that tumorspecific T cells from the peripheral blood of cancer patients exert potent responses in vitro, but T cells isolated from the tumor tissue were rather unresponsive [77]. T cells exposed to chronic antigen stimulation, such as during viral infection and cancer progression, became functionally impaired and displayed an exhausted phenotype [78].…”

“…In addition to the increased expression of inhibitory receptors, the impairment of T cell responses in the tumor tissue is characterized by changes in the signaling machinery of the TCR complex [77]. These include decreased expression of the adaptor molecule CD3ζ, tyrosine kinases Lck and Fyn and reduced expression of NF-κB family members that were correlated with impaired cytokine production by cytotoxic T lymphocytes.…”