Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

Abstract

Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.

Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia

“…By counteracting TCR-dependent signaling, PD-1 prevents CTLs from forming functional ISs [1,19]. To assess whether PD-1 overexpression induced in healthy CTLs by CLL-conditioned media is causal to their IS assembly defects, PD-1 neutralizing antibodies were added to CTLs cultured as in figure 1A, immediately prior to conjugate formation with SAg-pulsed Raji cells.…”

“…During their growth, tumors develop mechanisms for harnessing immune responses. CTLs are subjected to these suppressive actions, as demonstrated by impairment in their anti-tumoral functions [1]. Direct inhibitory receptor/ligand axes contribute to CTL suppression by inhibiting TCR-dependent signaling pathways [1].…”

“…CTLs are subjected to these suppressive actions, as demonstrated by impairment in their anti-tumoral functions [1]. Direct inhibitory receptor/ligand axes contribute to CTL suppression by inhibiting TCR-dependent signaling pathways [1]. Here we identify a new cell contact-independent mechanism of CLL cell escape from CTL-mediated killing.…”

“…PD-1 is almost absent in resting T cells while it is a hallmark of effector T cells [1,38,39]. Several stimuli upregulate PD-1 expression, the most important being TCR-mediated signaling, which activates transcription factors implicated in PD-1 expression, including nuclear factor of activated T cells 1 (NFATC1) [40,41], NF-κB [42], and T-bet [41].…”

“…To escape immune surveillance, neoplastic B cells of hematologic malignancies implement strategies that shape T lymphocytes of the tumor microenvironment (TME) toward an exhausted phenotype, characterized by increased expression of exhaustion markers and inability to produce adequate levels of immune-activating cytokines, which both contribute to T-cell dysfunctions [1]. T-cell suppression strategies are exploited by tumor cells of chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries.…”