Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers

Abstract

Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of Beta-2-microglobulin (B2M) mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients’ survival under ICB. Twenty-five patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab/ipilimumab. Sequencing was performed to determine B2M mutation status. B2M mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. B2M mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% vs. 46.6%, p>0.99) and survival (median PFS: 19.5 vs 33.0 months, p=0.74; median OS 39 months vs. not reached, p>0.99) were observed between B2M-mutant and B2M-wild type tumor patients. Among metastatic MSI GI cancers, B2M-mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in B2M-mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with B2M-mutant MSI cancer may be longer than of patients with B2M-wild type MSI cancer.

A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8+T Cells

“…While some studies to date have indeed highlighted a possible prognostic benefit to tumor MHC-I loss, these have often attributed such benefit to a sudden conferred susceptibility to NK cell-mediated killing [10, 40, 43]. Strikingly, however, we demonstrate that NK cells are not required for the efficacy of an ICB-involving regimen employed against MHC-I-negative tumors.…”

“…Within GBM alone, for instance, two separate studies gathering single cell RNA sequencing data from human tumors have found β2m expression to be inversely correlated with survival [11, 44]. Likewise, additional studies have implied that MHC-I loss does not necessarily render tumor cells invulnerable to CD8 + T-cell dependent immunotherapies, including ICB [10, 45]. The perception of MHC-I loss as a means of cancer immune-escape, then, is perhaps best described as controversial.…”

“…Recent pre-clinical and clinical studies, however, have demonstrated somewhat mixed roles for MHC-I and β2m in dictating responses to cancer immune-based platforms, such as immune checkpoint blockade (ICB). While some have suggested that resistance to ICB emerges through inactivation of tumor antigen presentation [7–9], for instance, others have implied that low tumor β2m and MHC-I expression are instead associated with favorable prognosis [10, 11]. These mixed findings highlight the need for further investigation into the role of tumor MHC-I, as well as revisiting traditional notions of anti-tumor immunity.…”

Upfront progression under pembrolizumab followed by a complete response after encorafenib and cetuximab treatment in BRAF V600E‐mutated and microsatellite unstable metastatic colorectal cancer patient: A case report

“…The biallelic beta‐2‐microglobulin (B2M) mutation, present in about 30% of MSI CRC, is another potential key mechanism of resistance towards ICI by non‐functionality of tumor cells' antigen presentation machinery 20,21 . The B2M mutated phenotype is associated with peritoneal and lymph node metastases, 22 and seems to be associated with a good prognosis in localized MSI CRC 23 . This mutation is not present in our patient and therefore does not explain a potential mechanism of primary resistance to pembrolizumab.…”

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

“…The degree of β2M LOH was tripled in non-responders (approximately 30%) when compared with responders (approximately 10%) and was correlated with inferior OS ( 41 ). Apart from melanoma, the links between β2M alteration and acquired resistance have been reported in lung cancer ( 42 ), gastrointestinal adenocarcinoma ( 43 ), and colorectal cancer with a microsatellite instability–high (MSI-H) phenotype ( 44 ).…”