A build-up of toxic, misfolded proteins causes cancer immunotherapy to fail

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"A build-up of toxic, misfolded proteins causes immune cells to become exhausted and might make cancer immunotherapy less effective. Researchers examined the proteins inside exhausted T cells taken from mice with colon and bladder tumours. Instead of slowing protein synthesis in response to stress, these T cells ramped up the production of misfolded proteins, creating a ‘proteotoxic stress response’ that overwhelmed the cell. This pathway could be targeted as a way to prevent T-cell exhaustion and boost cancer immunotherapies ..."

From the abstract:

"Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies. The mechanisms that underlie T cell exhaustion remain poorly understood.

Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer.

We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells.

We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR.

Contrary to canonical stress responses that induce a reduction in protein synthesis, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins.

Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling.

Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models.

Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy.

Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy."

Nature Briefing: Cancer

Proteotoxic stress response drives T cell exhaustion and immune evasion (open access)

Fig. 1: PSR is triggered in Tex cells with a dynamic expression of chaperone proteins.