Majority of B2M-Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High

Abstract

PURPOSE Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). B2M mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize B2M-mutant, IO-naive CRC. PATIENTS AND METHODS All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for B2M mutations. All B2M-mutant CRCs were assessed for expression of B2M, major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3+ and CD8+ tumor-infiltrating lymphocyte counts against a control group of MSI-H B2M wild-type CRCs. RESULTS Fifty-nine (3.4%) of 1,751 patients with CRC harbored B2M mutations, with 84% (77 of 92) of the mutations predicted to be truncating. B2M mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring B2M mutations (P < .001). Thirty-two of 44 B2M-mutant CRCs with available material (73%) had complete loss of B2M expression, whereas all 26 CRCs with wild-type B2M retained expression (P < .001). B2M mutation status was not associated with major histocompatibility complex class I expression, KRAS or BRAF mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with B2M-mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria. CONCLUSION B2M mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of B2M expression. Most patients with B2M-mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

“…Mutations in the JAK1/2 and inactivation of B2M can confer resistance to checkpoint-inhibiting immunotherapy 15,41,42 . Although in MSI colorectal cancer it has been shown that most patients with B2M inactivation benefitted from immunotherapy 43 , our data suggest that B2M loss can be subclonal and is not necessarily propagated to metastases. How subclonal immune evasion drivers and their localization in primary tumours or in metastases impairs immune checkpoint-inhibitor efficacy in dMMR GOAs should be investigated by MSeq in larger, immunotherapy-treated cohorts.…”

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

“…Mutations in the JAK1/2 and inactivation of B2M can confer resistance to checkpoint-inhibiting immunotherapy 15,39,40 . Although in MSI colorectal cancer it has been shown that most patients with B2M inactivation benefitted from immunotherapy 41 , our data suggests that B2M loss can be subclonal and is not necessarily propagated to metastasis. How subclonal immune evasion drivers and their localisation in the primary tumours or in metastases impairs immune checkpoint-inhibitor efficacy in dMMR GOAs should be investigated by MSeq in larger, immunotherapy treated cohorts.…”

Therapeutic Targeting of the Colorectal Tumor Stroma

“…Analyses of primary tumors and metastases from the same patients provided evidence for immune selection of malignant cells 80 . This mechanism is prevalent in MSI tumor cells, which often lose membrane HLA molecules, [81][82][83] so they escape T-cell cytotoxicity but not NK cell cytotoxicity. This reduces their metastatic potential 52 Fusobacterium nucleatum, which are associated with lower densities of T cells 90 , lymph node metastasis 89 , and poor outcomes, 91 require further study 92 .…”