TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion

Abstract

T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9–mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell–based cancer immunotherapies.

Visualizing and manipulating hyperstabilization of T cell microvilli contacts by engineered chimeric antigen receptors

“…3m-n ) but when we shifted these cultures to hypoxia, mimicking the tumor microenvironment and licensing deeper progression into exhaustion (Scharping et al, 2021), the conventional high affinity dimer was more susceptible to exhaustion as measured by TOX and PD1 co-expression ( Fig. 5i ), in line with recent work (Shakiba et al, 2021) using native TCRs.…”

“…Recent work shows that even within natural TCR affinity ranges, there is a "sweet spot" for binding strength (Shakiba et al, 2021). We thus sought to understand how CARs interact with the natural cell biology, relative to TCRs, and how varying the binding dynamics of an antigen receptor affects topographical antigen scanning.…”

T cell Egress via Lymphatic Vessels Limits the Intratumoral T cell Repertoire in Melanoma

“…In addition to issues of antigen access, CD8 + T cell function in the TME is dictated by both antigen affinity and abundance 37, 56, 57 . We found that the probability of T cell egress, as measured by CXCR4 and ACKR3 surface expression, was dependent on the strength of TCR stimulation, where low affinity antigen encounter (e.g., endogenous, self-antigens) was insufficient to promote retention.…”

CD8 agonism functionally activates memory T cells and enhances antitumor immunity

“…31 Recently, it was reported that T cells with high or low antigen affinity are equally unable to inhibit tumor growth due to either dysfunction or inadequate engagement of the effector machinery, respectively. 32 Genetic ablation of Cd8a in cells with high affinity TCRs decreases their avidity, protects them from rapid exhaustion and increases their antitumor function. We observed a slight downregulation of CD8β after treatment with CD8 mAb, enhanced proximal TCR signaling and effector cytokine production and better tumor control.…”