Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids

Abstract

Patients treated with immune checkpoint blockade (ICB) sometimes experience immune-related adverse events (irAEs), requiring immuno-suppressive drugs such as corticosteroids despite the possibility that immunosuppression may impair the antitumor effects of ICB. Here, we address the dilemma of using corticosteroids for the treatment of irAEs induced by ICB. ICB augments neoantigen-specific CD8+ T cell responses, resulting in tumor regression. In our model, simultaneous, but not late, administration of corticosteroids impaired antitumor responses with reduction of CD8+ T cell proliferation. Secondary challenge using tumors with/without the neoantigen showed selective progression in tumors lacking the neoantigen when corticosteroids were administered. Corticosteroids decreased low- but not high-affinity memory T cells by suppressing fatty acid metabolism essential for memory T cells. In a small cohort of human melanoma patients, overall survival was shorter after treatment with CTLA-4 blockade in patients who received early corticosteroids or had low tumor mutation burden. Together, low-affinity memory T cells are dominantly suppressed by corticosteroids, necessitating careful and thoughtful corticosteroid use.

Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?

“…A subgroup analysis according to irAE type or severity suggested that only cutaneous or endocrine irAEs as well as mild irAEs (grade 1 or 2) can be associated with better treatment outcomes. This was possibly due to the unnecessity for permanent discontinuation of ICI treatment [7] or for high-dose systemic glucocorticoid treatment, which can counteract antitumor immunity induced by ICI therapy [8]. These findings require a further clinical examination for verification, however.…”

An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+T cell dysfunction in the tumor microenvironment

“…Further, another recent study showed that low-affinity memory T cells are inhibited by corticosterone and that overall survival (OS) was reduced in melanoma patients who received corticosteroids along with ICB (Tokunaga et al, 2019). These observations highlight the need to understand the effects of low-versus high-dose administration of exogenous glucocorticoids and how these relate to the effects of endogenous glucocorticoid.…”

Dexamethasone premedication suppresses vaccine-induced immune responses against cancer

“…A recent paper also reported that simultaneous, but not delayed administration of corticosteroids impaired neo-antigen specific anti-tumor responses augmented by checkpoint blockade. 15 Reduced CD8 + T-cell proliferation and lack of protection upon rechallenge with tumors lacking the neoantigen were observed. Here, corticosteroids were shown to decrease low-but not high-affinity memory T cells by suppressing fatty acid metabolism essential for memory T cells.…”

“…A limited set of data indicates that Dexa administration is associated with poorer outcome of cancer patients in general [9][10][11][12] and that it specifically interferes with immune-checkpoint blockade as well as chemotherapy. [13][14][15][16] We are developing cancer vaccines which are based on tumor-antigen encoding RNA. Being a natural TLR7/8 ligand, RNA has intrinsic adjuvant activity and the antigen is delivered in an HLA-independent manner.…”