Response to pembrolizumab in metastatic colorectal cancer with microsatellite instability and markedly reduced HLA-I expression suggests NK cell involvement

Abstract Despite growing enthusiasm for immunotherapy in cancer treatment, only a few colorectal cancer (CRC) patients experience lasting therapeutic effect. This limited efficacy is likely driven by different tumor-intrinsic resistance mechanisms, including loss or downregulation of HLA-I molecules, which may impair antigen presentation and cytotoxic T cell recognition. Interestingly, the downregulation of HLA-I can augment tumor susceptibility to natural killer (NK) cell attack. However, NK cell activity may be inhibited by immunosuppressive signals within the tumor microenvironment. This study describes two patients with metastatic CRC and microsatellite instability who showed durable responses to pembrolizumab despite unfavorable prognostic factors (tumor recurrence, BRAF V600E mutation and markedly reduced HLA-I on tumor cells). Tumor samples obtained at surgical resection also revealed PD-L1 expression on tumor cells and a substantial fraction of tumor-infiltrating PD-1 + NK cells. These findings raise the hypothesis that PD-1/PD-L1 blockade may have contributed to NK-cell-mediated antitumor activity in the context of markedly reduced HLA-I expression. Furthermore, assessing PD-L1 and HLA-I expression on tumor cells at diagnosis could help identify patients who could benefit most from pembrolizumab treatment, alone or combined with inhibitors of HLA-I-specific inhibitory NK receptors. These observations provide a rationale for further investigation in larger and multicenter patient cohorts.