A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors

Abstract

Approximately half of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors do not respond to PD-1 blockade, indicating the importance of the identification of predictive biomarkers associated with less responsiveness to PD-1 blockade. Among 45 MSI-H/dMMR gastrointestinal (GI) tumors, a low tumor mutational burden (TMB) and PTEN mutations were mutually exclusive and were associated with poor clinical outcomes to PD-1 blockade. PTEN mutations in the phosphatase domain were associated with lower responsiveness to PD-1 blockade together with decreased CD8 + T cells and increased tumor-associated macrophages, while those in the C2 domain were not. Importantly, among 20 patients showing disease progression within 6 months after PD-1 blockade, 4 had a low TMB (20%), and 8 had PTEN phosphatase domain mutations (40%). Other gene alterations, such as STK11, FBXW7, JAK1, B2M, and HLA mutations, were also observed in non-responders.Research.

Case Report: Immune and Genomic Characteristics Associated With Hyperprogression in a Patient With Metastatic Deficient Mismatch Repair Gastrointestinal Cancer Treated With Anti-PD-1 Antibody

“…TMB is a reliable efficacy factor for immunotherapy (11,(18)(19)(20)(21). Studies have demonstrated that those with low TMB, as seen in this case, showed less favorable survival rate (11,17,18,(20)(21)(22)(23)(24). MSI-H/ dMMR tumors are identified with high clonality of nonsynonymous mutations (also high TMB), leading to the presence of robust altered proteins, known as neoantigens (25).…”

“…Optimal TMB cut-offs vary among different studies. However, levels lower than 10 Muts/Mb are generally categorized as low (1,11,17). TMB is a reliable efficacy factor for immunotherapy (11,(18)(19)(20)(21).…”

Association of PIK3CA mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma

“… 15 , 22 , 30 Recent studies have shown that activation of the PI3K pathway regulates tumor-intrinsic and immune-intrinsic features of the immunosuppressive tumor microenvironment. 53 , 54 In particular, PTEN abrogation generates an immune-suppressive microenvironment by altering cytokine secretion patterns. 8 Moreover, a few studies have indicated that activation of PI3K signaling may promote immune escape through regulating PDCD1 (PD-1)/CD274 expression.…”

Long-Term Response to Gemcitabine, Cisplatin, and Nab-Paclitaxel Followed by Maintenance Therapy for Advanced Gallbladder Cancer: A Case Report and Literature Review

“…In addition, the binding of PD-1 and PD-L1 in the tumor microenvironment can inhibit T-cell activity and promote tumor cell evasion of immune surveillances (30). Thus, low PD-(L) 1 expression is associated with better prognosis (31,32). Because GBC was a highly aggressive malignant tumor prone to local infiltration and hematogenous metastasis at an early stage, we performed a tumor microenvironment assay on the postoperative specimen of this patient, which might reflect the tumor immune microenvironment of the patient after recurrence to some extent.…”