B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy

Abstract

β2-microglobulin (B2M) and Janus kinases 1 and 2 (JAK1/2) mutations have been suggested as genetic mechanisms of immune evasion for anti-programmed cell death protein 1 (PD-1) therapy. Whether B2M and JAK1/2 lose-of-function mutation can cause primary resistance to anti-PD-1 therapy in colorectal carcinoma (CRC) patients remains controversial. Here, we sought to compare the efficacy of anti-PD-1 therapy in DNA mismatch repair deficient/microsatellite instability-high CRC patients with or without B2M or JAK1/2 mutations. Thirty-Five CRC patients who received anti-PD-1 therapy were enrolled in this study. All tumor samples underwent nextgeneration sequencing. The clinical and molecular data from 110 CRC patients sequenced with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay and accessed through cBioportal were also analyzed in this study. Of the 35 CRC patients from our center, 10 (28.6%) had a B2M lossof-function mutation, and 8 (22.9%) had a JAK1/2 loss-offunction mutation. Compared with B2M wild-type CRCs, B2M-mutated CRCs did not show a higher frequency of resistance to anti-PD-1 therapy (P = 0.71). There was even better response to anti-PD-1 therapy in patients with JAK1/2 mutation than in those without (P = 0.015). Of the 110 CRC patients in the MSK-IMPACT datasets, 13 (11.8%) had a B2M mutation, and 15 (13.6%) had a JAK1/2 mutation. After analyzing the response to anti-PD-1 therapy in these 110 patients, we found similar results (P = 0.438 and 0.071, respectively). Moreover, patients with B2M or JAK1/2 mutation had a lower tumor mutational burden score compared with those without. B2M and JAK1/2 loss-of-function mutations occur frequently in microsatellite instability-high CRC. Our study demonstrated that patients with CRC harboring B2M or JAK1/2 mutations should not be excluded from anti-PD-1 therapy.

TKI for immunotherapy refractory in MSI-H colorectal cancer: a case report

“…A study by Yang et al found that B2M mutation was an indicator of immunotherapy resistance in pan-cancer species [9]. While Ding et al con rmed that immunotherapy resistance-related gene B2M mutation did not affect the bene t of MSI-H colorectal cancer patients from anti-PD1 immunotherapy [10]. Meanwhile, the patient refused any kind of chemotherapy.…”

Comprehensive analysis of mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs): A SEER database analysis of 767 cases

“…Neoadjuvant chemotherapy and adjuvant chemotherapy significantly improve survival of several cancers, and the immunotherapies by targeting immune check points, are successfully used in certain cancers ( 27 – 29 ). In this study, we could not analyze these important aspects of multimodal and novel therapies, as there was not sufficient information available.…”

Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy

“…However, according to a recent meta-analysis, BRAF mutations do not influence the response to ICI, while remaining a negative prognostic biomarker [ 236 ]. The association between oncogenic mutations with ICI resistance in MSI CRC was not confirmed for B2M , HLA , and JAK1/2 , although these genes were found to be frequently mutated in MSI CRC [ 46 , 47 ].…”

“…At the same time, about a quarter of metastatic colorectal cancers and up to half of some other types of cancer are intrinsically resistant to ICI [ 43 , 44 ]. Several mechanisms of such an intrinsic resistance have been proposed, including the activating mutations in the RAS/RAF signaling pathway [ 45 ], mutations in the antigen presentation machinery and interferon pathway genes [ 46 , 47 ], establishment of an immunosuppressive microenvironment [ 48 ], as well as the influence of the gut microbiome [ 49 ] and immunoediting theory [ 50 ].…”