Improvement of PD-1 Blockade Efficacy and Elimination of Immune-Related Gastrointestinal Adverse Effect by mTOR Inhibitor

Abstract

During the past decades, immunotherapy, especially the antibody-mediated immune checkpoint blockade (ICB) has shown durable tumor inhibition and changed the paradigm of cancer treatment. However, a growing body of evidence suggests that ICB treatment induces severe immune-related adverse events (irAEs), and the side effect even leads to the discontinuation of lifesaving treatment. Here, we found that ICB treatment induces colitis in melanoma patients and promotes the infiltration of CD8+ effector T cells into colitic lesions. Further transcriptomic dissection indicated the PI3K-AKT-mTOR pathway was highly activated in CD8+ effector T cells of colitic lesions. Moreover, we developed a mouse melanoma model to recapitulate the gastrointestinal toxicity of anti-PD-1 treatment in clinical settings. Anti-PD-1 treatment significantly contributed to the infiltration of CD8+ T cells, and correspondingly induced severe enteritis. Immunohistochemistry experiments showed that the PI3K-AKT-mTOR pathway of T cells was activated by anti-PD-1 treatment. Blockade of the pathway with mTOR inhibitor sirolimus not only inhibits tumor growth but also suppresses the T cell infiltration in colitic lesions. More importantly, combination with sirolimus and anti-PD-1 synergistically inhibits tumor growth via inducing the immunogenic cell death of tumor cells in vivo. In summary, our research demonstrated the principle of mTOR inhibitor and anti-PD-1 combinatorial therapeutic regimen, which provided a novel therapeutic strategy for irAEs in clinics.

Crosstalk Between Metabolism and Immune Activity Reveals Four Subtypes With Therapeutic Implications in Clear Cell Renal Cell Carcinoma

“…In addition, the findings of several studies indicated that ICI therapy can have the potential to influence the cross-communication between tumors and T cells. The inhibition of the PD-1-PD-L1 axis in tumor cells can dampen aerobic glycolysis via suppression of the PI3K–AKT–mTOR pathway ( 35 – 37 ). As a result, the function of TILs would be restored with the increase in available glucose.…”

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

“…Fortunately, immunotherapies, especially the antibodymediated immune checkpoint blockade (ICB), have shown durable tumor inhibition in the treatment of metastatic melanoma during the past decade year (Hodi et al, 2010;Hamid et al, 2013;Larkin et al, 2015;Robert et al, 2015). Several monoclonal antibodies targeting CTLA-4 and PD-1/PD-L1 have been approved to treat advanced melanoma and various malignant tumors which significantly prolonged patient survival (Hargadon et al, 2018;Bai et al, 2021;Carlino et al, 2021). In a series of clinical trials, nivolumab or pembrolizumab (anti-PD-1 antibody) treatment approached objective overall response rates from 10% to 40% and extended the median overall survival to 10.1 months (Robert et al, 2015;Robert et al, 2021).…”

Neutrophil extracellular traps (NETs)-related lncRNAs signature for predicting prognosis and the immune microenvironment in breast cancer

“…Some studies have reported that the combination of rapamycin and other chemotherapeutic agents can improve the efficacy ( Niu et al, 2011 ; Sun et al, 2021 ). In addition, the combination with rapamycin and anti-PD-1 synergistically inhibits tumor growth and mitigates immune-related colitis in a mouse melanoma model ( Bai et al, 2021 ). Thus, methotrexate and rapamycin are promising for the treatment of adverse events caused by immunotherapy.…”