Data from Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair–Deficient Colorectal Cancer

Abstract

<div>AbstractPurpose:<p>Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking.</p>Experimental Design:<p>Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response.</p>Results:<p>The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while <i>HLA-DQA1</i> and <i>HLA-DQB1</i> were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8<sup>+</sup> T-cell density was associated with pCR response (767.47 per.mm<sup>2</sup> vs. 326.64 per.mm<sup>2</sup>, <i>P</i> = 0.013 Wilcoxon test). Further integrated analysis showed that CD8<sup>+</sup> T cells with low PD-1 expression (PD-1<sup>lo</sup> CD8<sup>+</sup> T cells) expressing high levels of <i>TRGC2, CD160,</i> and <i>KLRB1</i> and low levels of proliferated and exhausted genes were significantly associated with pCR response.</p>Conclusions:<p>Immune-associated transcriptomic features, particularly CD8<sup>+</sup> T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.</p></div>