Two cases of intrahepatic cholangiocellular carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade

Abstract

Background: Insertion-deletion mutations (indels) may generate more tumour-specific neoantigens with high affinity to major histocompatibility complex class I. A high indel ratio is also related to a good response to programmed death-1 (PD-1) checkpoint blockade in melanoma and renal cell carcinoma. However, the correlation between a high indel ratio and the immunotherapy response in intrahepatic cholangiocarcinoma (ICC) is unknown.

Case presentation: Two patients with relapsed ICC at stage IIIb were treated with PD-1 blockade combined with chemotherapy. After 7 and 4 months of chemotherapy and PD-1 blockade (3 and 15 cycles, and 5 and 6 cycles, respectively), magnetic resonance imaging and positron emission tomography with computed tomography imaging showed that both patients achieved a complete response (CR), which has lasted up to nearly 16 and 13 months to date, respectively. Whole-exome sequencing and immunohistochemistry analysis showed that both patients had cancers with microsatellite stability (MSS) and mismatch repair (MMR) proficiency, weak PD-L1 expression, and a tumour mutation burden (TMB) of 2.95 and 7.09 mutations/Mb, respectively. Patient 2 had mutations of TP53 and PTEN that are known to confer sensitivity to immunotherapy, and the immunotherapy-resistant mutation JAK2, whereas patient 1 had no known immunotherapy response-related mutations. However, the indel ratios of the two patients (48 and 66.87%) were higher than the median of 12.77% determined in a study of 71 ICC patients. Moreover, comparison to six additional ICC patients who showed a partial response, stable disease, or progressive disease after PD-1 blockade treatment alone or in combination with chemotherapy demonstrated no difference in PD-L1 expression, TMB, MSI, and MMR status from those of the two CR patients, whereas the indel frequency was significantly higher in the CR patients.

Conclusions: These two cases suggest that indels might be a new predictor of PD-1 blockade response for ICC patients beside PD-L1 expression, TMB, MSI, and dMMR, warranting further clinical investigation.

Keywords: Combination immunotherapy; Indel; Intrahepatic cholangiocarcinoma; PD-1 blockade; Whole-exome sequencing.

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The two patients provided informed consent.

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The authors declare that they have no competing interests.

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Figures

Fig. 1

Imaging of patient 1 over the course of therapy. a showed timeline of the clinical course. Representative micrographs of PD-L1 expression (b) and percentage of CD8+ T cells (c) within tumor (original magnification ×400). The positive rate of PD-L1 and CD8+ T cells were < 5% and 10%, respectively. MRI and PET-CT imaging (d) showed the lesion around the margin and enlarged lymph nodes disappeared after treatment with pembrolizumab in combination with tegafur on September 14, 2017. The CR was sustained up to 9 January 2019

Fig. 2

a Timeline of the clinical course in patient 2. The positive rate of PD-L1 (b) and CD8+ T cells (c) in patient 2 were < 5% and 10% evaluated by IHC, respectively (magnification ×400). Patient 2 had a complete metabolic response after treatment with pembrolizumab in combination with tegafur, with no residual hypermetabolic uptake on post-treatment imaging (d)